Bridged-Cyclo-ProTides as Prodrugs of Therapeutic Nucleosides and Nucleotides

ABSTRACT

Provided herein are bridged cyclic phosphates and phosphoramidates (bc-ProTides) of nucleosides, which is a compound, its stereoisomers, isotope-enriched analogues, pharmaceutically acceptable salts, hydrates, solvates, or crystalline or polymorphic forms thereof, with the following structure: 
     
       
         
         
             
             
         
       
     
     These compounds can be used for the treatment of viral infections and/or neoplastic diseases in mammals. By optimizing combinations of Y 2 , Y 3 , R 0 , and M, the cleavability of these compounds as prodrugs can be attuned for different tissue targeting with various functional combinations. Also disclosed are processes and methods for preparation of these compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

The present applications claims the benefits of U.S. ProvisionalApplication Ser. No. 61/955,240, the entire said invention beingincorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds, their preparation methods,and uses as medicinal agents in treatment of viral infections and/orneoplastic diseases. 3′,5′-Bridged cyclic phosphates andphosphoramidates formed by a 5′-P, 3′-O-linker of tunable cleavabilityas prodrugs (bc-ProTides) for active nucleotides, usually nucleotidetriphosphates, are provided which allow concentration of active drugs indiseased tissues such as infected hepatic tissues.

BACKGROUND OF THE INVENTION

Nucleoside analogues are highly effective agents for treatment of viralinfectious diseases such as AIDS, hepatitis B, herpes virus, herpeszoster, cytomegalovirus and the like. A large number of significantknown compounds include Entecavir, Abacavir, Lamivudine, Tenofovir,Adefovir, Acyclovir, Ganciclovir, Famciclovir, Lobucavir and the like.Nucleoside analogues, such as Gemcitabine, Cladribine (2-CdA),Fludarabine, Clofarabine, Nelarabine and the like, are effective fortreatment of neoplastic diseases. It is expected that nucleosideanalogues should also play a pivotal role in anti-HCV and anti-DENVtreatment with one recently approved nucleotide (Sofosbuvir) of thiskind and several nucleoside analogues in late stage clinicaldevelopments at the present time.

Most of anticancer and antiviral nucleoside analogs require metabolicactivation to the 5′-mono, di-, and triphosphates via sequentialphosphorylation by nucleoside and nucleotide kinases. Inefficientmetabolic activation has been known to be among causes of the lack oftherapeutic effectiveness of many nucleoside analogs, and as animportant mechanism of nucleoside drug resistance. In these cases,usually the first phosphorylation step is rate limiting, thus theactivity of these nucleosides can be rescued by various phosphate andphosphonate prodrug strategies. A variety of nucleoside monophosphateprodrugs (pronucleotides or ProTides), such as aryloxy phosphoramidatediesters, bisPOM, cycloSAL, hepDirect, and SATE, have been developed toimprove their therapeutic activity by increasing the intracellularuptake of mono-phosphorylated nucleoside drugs. Prominent examplesinclude Adefovir dipivoxil, Tenofovir disoproxil, and Sofosbuvir(GS-7977). However, existing ProTides have issues such as intracellularrelease of toxic agents (aryl alcohols, aryl vinyl ketone, ethylenesulfide, etc.), poor stability, varieties in intra- and interpatientpharmacokinetic and pharmacodynamic profiles, and low yields insynthesis. As an example, INX-189 produces intracellularly 1-naphthol,which, in addition to postulated mitochondrial toxicity of the resultingnucleotide, potentially caused the failure of this compound. As anotherexample, Sofosbuvir, a clinical anti-HCV drug, is an aryloxyphosphoramidate diester and releases toxic phenol.

3′,5′-Cyclic phosphates and phosphoramidates of nucleotides have beendeveloped as uncommon prodrug structures to deliver nucleoside5′-phosphates into cells with the expectation of improved cellularuptake by reducing the rotational degrees of freedom with aconformationally constrained structure and blocking the 3′-hydroxylgroup to reduce polarity, and also removing toxic phenol or 1-naphthol.A variety of derived prodrug forms include phosphoramidate, SATE,pivaloyloxymethyl (POM), and simple alkyl ester groups as substituentsof such 3′,5′-cyclic phosphates and phosphoramidates. One notableexample is PSI-352938, a suspended investigational drug for anti-HCVtreatment because of the observed elevated level of liver enzymes inpatients in clinical trials. It was reported that PSI-352938 wasactivated to nucleoside 5′-phosphates via a key step of selective ringopening by phosphodiester cleavage of the 3′-phosphate-oxygen bondcatalyzed by cyclic nucleotide phosphodiesterase (PDE) enzymes. Webelieve this PDE-mediated hydrolytic activation be shared by all3′,5′-cyclic phosphate and phosphoramidate prodrugs, may impact thetightly regulated cellular cyclic nucleotide signaling pathways, whichare temporally, spatially, and functionally compartmentalized, andresult in abnormal intracellular concentrations of cyclic nucleotides(such as cAMP and cGMP), and, consequently, myriad biological responsesleading to human diseases. These cyclic nucleotides may also act assecondary messengers and lead to undesired physiological changes, withtheir median effective concentrations (EC₅₀) in or close to the range ofapparent activation constants (K_(a)) of protein kinase A (PKA RIβ₂:C₂,29 nm; RIα₂:C₂, 101 nm; RIIα₂:C₂, 137 nm; and RIIβ₂:C₂, 584 nm) for cAMPand of protein kinase G (PKG-Iα, 67 nm and PKG-Iβ, 133 nm) for cGMP.

Therefore, there are needs for better pronucleotides. To minimizecytotoxicity, properties of tissue targeting (i.e. concentration ofactive drugs in liver tissues based on ProTide strategy), no release ofcytotoxic metabolites, and clearance of disrupting nontargeted vitalcellular/biological processes (off-target effects) by the prodrug andits intermediates are extremely attractive.

SUMMARY OF THE INVENTION

This invention provides novel compounds of nucleoside bridged cyclicphosphate and phosphoramidates with a cleavable linker/bridge for use asprodrugs in treatment of viral infections and/or anti-neoplasticdiseases in mammals, which is a compound, its stereoisomers,isotope-enriched analogues, salts (acid or basic addition salts),hydrates, solvates, or crystalline forms thereof, represented by thefollowing structure (Formula I):

wherein

(a) R is a moiety derivable by removal of 3′- and 5′-hydroxyl radicalsfrom a therapeutic nucleoside or its equivalents.

(b) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to represent a phosphonate or phosphonamidate;

(c) X₁ is O, S or Se;

(d) PR⁰ is selected from: (i) phosphate, or phosphoramidate representedby PY₄R² where Y₄ is O, S, Se, or NR^(8′″); (ii) phosphoramidate ofamino acid esters or amides, or of esters or amides of modified aminoacids, represented by PY₁[C(R^(1a)R^(1b))]_(d)C(═X₂)Y₄R² where Y₁ isNR⁸, X₂ is O, S or Se, and Y₄ is O, S, Se, or NR^(8′″);

(e) M is a molecular bridge selected from CR^(5a)R^(5b),(CR^(5a)R^(5b))_(d)OC(═O), and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to4;

(f) Y₁, Y₂, Y₃, and Y₄ are selected as follows: (i) Y₁ is selected fromO, S, Se, and NR⁸; (ii) Y₂ is selected from O, S, Se, and NR^(8′); (iii)Y₃ is selected from O, S, Se, and NR^(8″); (iv) Y₄ is selected from O,S, Se, and NR^(8′″); (v) R⁸ and R^(1a) or R^(1b) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where n is 2 to 4, and Y₁ is NR⁸; (vi) R^(8′) and R^(5a) or R^(5b)together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4 and Y₂ is NR^(8′); (vii)R^(8″) and R^(5a) or R^(5b) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4, and Y₃ is NR^(8″); (viii) Y₃ is O, M is CR^(5a)R^(5b)C(═O), and Y₂ isNR^(8′), so that Y₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a naturalor modified α-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S;(ix) the said modified α-amino acids can be a β-, γ-, or δ-amino acid orits analogues represented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2to 4; (x) Y₂ can be O or S of an α-amino acid residue as in serine (OH),threonine (OH), and cysteine (SH), and the amino can be substituted orunsubstituted;

(g) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(h) R⁸, R^(8′), R^(8″), and R^(8′″) are independently selected fromhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸, R^(8′), R^(8″), or R^(8″) in Y_(x) can be the sameor different groups where x is 1 to 4;

(i) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl, heteroaryl, arylalkyl(C₁-C₃), andheteroarylalkyl(C₁-C₃), where c is 1 to 6, d is 0 to 2, e is 0 to 3, andsaid aryl groups are optionally substituted with a group selected fromhydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, andwhere R^(1′) is hydrogen or alkyl, which includes, but is not limitedto, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) isH and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(CH₂)_(m) so as to form a spiro ring, where m is 2 to 5; (vi) R^(1a) ishydrogen and R^(1b) and R⁸ together are (CH₂)_(n) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4 and Y₁is NR⁸; (vii) R^(1b) is hydrogen and R^(1a) and R⁸ together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, where n is 2 to 4 and Y₁ is NR⁸;

(j) R^(5a) and R^(5b) are selected as follows: (i) R^(5a) and R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8′), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;

Provided herein are compounds, comprising 3′,5′-bridged cyclicphosphates or phosphoramidates. The molecular bridge (M) can be selectedfrom acetal, ketal, thioacetal, thioketal, oxymethylamide, and N-Mannichbase of a general structure (Y₂—C(R^(5a)R^(5b))-3′-Y₃), or be a lactone(Y₂—C(R^(5a)R^(5b))C(═O)-3′-O) or a carbonate ester(Y₂—C(R^(5a)R^(5b))OC(═O)-3′-O). The other substituent on the phosphoruscenter can be an alkoxyl, a thioalkoxyl, a cycloalkyloxyl, aheterocyclyloxyl, an aryloxyl, a heteroaryloxyl, an alkylamino, acycloalkylamino, a heterocyclylamino, an arylamino, a heteroarylamino,or a natural amino acid or modified amino acid so as to form aphosphoramidate or a phosphate ester. The oxo- of this phosphate orphosphoramidate group can be substituted by sulfur and selenium.Embodiments of these groups are described in detail herein.

Each of the compounds further comprises a structure moiety effectiveagainst viral infections or for treatment of neoplastic diseases, whichis a nucleoside with 3′-Y₃H and 5′-A₃H, or 5′-phosphonate or5′-phosophonamidate. It is believed that these compounds can betransformed into nucleotide monophosphate by enzyme mediated processesor spontaneous hydrolysis (Activation mechanism in FIG. 1 as anexample). With appropriate substituents, these masked drugs canselectively concentrate in diseased tissues such as infected livertissue, and be activated on site by tissue specific enzymes. Thus,potentially undesired distribution of the active drugs, and thus theirtoxicity in tissues such as gastrointestinal tract can be reduced.

In certain embodiments, compounds provided herein may be selectivelyconcentrated to liver tissues, lymphatic tissues, or other targetedtissues after oral administration, and metabolized to nucleotidemonophosphates, which are further phosphorylated by cellular kinases tothe active nucleotide phosphates. These phosphates can inhibit thetargeted enzymes. Thus optimal dose amounts can be reduced.

In certain embodiments, the structure moiety of antiviral oranti-neoplastic agent is a therapeutic nucleoside or potent nucleosiderecognized by persons skilled in the art for the treatments of suchconditions. The two moieties are bonded to form an 8-membered ring fusedwith sugar via a linker (Y₂—C(R₅R₆)-3′-Y₃) or to form a 9 to 12-memberedring fused with sugar via a linker (Y₂—(C(R₅R₆))_(d)C(═O)-3′-Y₃) or(Y₂—C(R₅R₆) OC(═O)-3′-Y₃), or the like, where Y₂ and Y₃ is independentlyO, S, or NR^(8″), and d is 1 to 4.

DETAILED DESCRIPTION OF THE INVENTION

This invention pertains to novel bridged cyclic phosphate andphosphoramidate compounds, their compositions, methods of preparations,and use in the treatments of viral infections and neoplastic diseases inhumans and animals.

DEFINITION

The definitions of terms used herein are consistent to those known tothose of ordinary skill in the art, and in case of any differences thedefinitions are used as specified herein instead.

The term “alkyl”, as used herein refers to a monovalent saturatedstraight or branched hydrocarbon radical, including both unsubstitutedand substituted alkyl groups. In certain embodiments, the alkyl groupincludes one to twenty carbon atoms, i.e., C₁-C₂₀ alkyl, more preferablyC₁-C₁₀ alkyl. In certain embodiments, the alkyl group is a primary,secondary, or tertiary hydrocarbon radical. In certain embodiments, thealkyl group is a halogenated alkyl group. In certain embodiments, thealkyl group is selected from the group consisting of methyl, CF₃, CF₂Cl,CFCl₂, CCl₃, ethyl, CH₂CF₃, CF₂CF₃, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,neohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, heptyl,octyl, isooctyl, nonyl, decyl, and dodecyl. Non-limiting examples ofoptional substituents are selected from the group consisting ofhydroxyl, amino, halogen (fluoro, chloro, bromo or iodo), alkylamino,arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate,phosphonic acid, phosphate, or phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art.

The term “cycloalkyl”, as used herein refers to a saturated cyclichydrocarbon radical. In certain embodiments, the cycloalkyl group may bebridged, and/or a fused bicyclic group. In certain embodiments, thecycloalkyl group includes three to ten carbon atoms, i.e., C₃-C₁₀cycloalkyl. Non-limiting examples are selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.1.1]hexyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]heptyl,decalinyl, or adamantyl.

The term “cycloalkylalkyl”, as used herein refers to an acyclic alkylgroup substituted by a cycloalkyl comprising of three to eight carbonatoms. Non-limiting examples are selected from the group consisting ofcyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.

“Alkenyl” refers to straight, branched, acyclic monovalent olefinicallyunsaturated hydrocarbon groups, having up to about 20 carbon atoms,preferably C₂-C₆, having at least one C═C bond. The term includes bothsubstituted and unsubstituted moieties. Non-limiting examples areselected from the group consisting of vinyl (—CH═CH₂), n-propenyl(—CH₂CH═CH₂), isopropenyl (—C(CH₃)═CH₂), butenyl, pentenyl, hexenyl, andthe like.

The term “cycloalkenyl”, as used herein refers to monovalent cyclichydrocarbon groups, having at least one C═C bond. In certainembodiments, cycloalkenyl refers to mono- or multicyclic ring systemsthat include at least one C═C bond. In certain embodiments, thecycloalkenyl group may be a bridged, non-bridged, and/or a fusedbicyclic group. In certain embodiments, the cycloalkenyl group includesthree to ten carbon atoms, i.e., C₃-C₁₀ cycloalkenyl.

“Alkynyl” refers to monovalent unsaturated hydrocarbon groups having atleast one C≡C bond. In certain embodiments, alkynyl refers tohydrocarbon radicals having up to about 20 carbon atoms which can bestraight-chained, branched, or cyclic, and having at least one C≡C bond.Non-limiting examples of alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH), and the like.

The term “aryl”, as used herein, and unless otherwise specified, refersto a monovalent unsaturated aromatic carbocyclic group such as phenyl,naphthyl, biphenyl, and the like. The aryl can be substituted orunsubstituted. An aryl group can be substituted with one or moremoieties selected from the group consisting of halogen (fluoro, chloro,bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino,arylamino, acyl, acyloxy, carboxyl, alkoxy, aryloxy, nitro, cyano,sulfonic acid, sulfate, phosphonic acid, phosphate, phosphonate, thiol,thioalkoxy, or other moieties as known to those skilled in the art.

“Alkoxy” refers to the group —OR′ where R′ is alkyl or cycloalkyl.Alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Alkoxycarbonyl” refers to a radical —C(═O)—OR′ where OR′ is alkoxy asdefined herein.

“Amino” refers to the radical —NH₂. The term “alkylamino” or “arylamino”refers to an amino group that has one or two alkyl or aryl substituents,respectively. In certain embodiments, the alkyl substituent is loweralkyl. In certain embodiments, the alkyl or lower alkyl is substitutedor unsubstituted. “Monoalkylamino” refers to the group —NR′H, wherein R′is selected from alkyl, cycloalkyl, and aryl.

“Carboxyl” or “carboxy” refers to the radical —C(═O)OH.

“Thioalkoxy” refers to the group —SR′ where R′ is alkyl or cycloalkyl.

The term “heterocyclyl” refers to a monovalent radical of monocyclicnon-aromatic ring group and/or multicyclic ring group that contains atleast one non-aromatic ring, wherein one or more of the non-aromaticring atoms are heteroatoms independently selected from O, S, N or P, andthe remaining ring atoms are carbon atoms. The heterocyclyl groups arebonded to the rest of the molecule through the non-aromatic ring, andmay be attached to the main structure at any heteroatom or carbon atomwhich results in the creation of a stable compound, and heterocyclic mayalso be optionally substituted. The heteroatoms (nitrogen, phosphorus,or sulfur) in a heterocyclyl group may be optionally oxidized, thenitrogen atoms may be optionally quaternized, and some rings may bepartially or fully saturated, or aromatic. In certain embodiments, theheterocyclyl or heterocyclic group has 3 to 20 ring atoms. In certainembodiments, the heterocyclyl may be monocyclic, bicyclic, tricyclic, ortetracyclic, which may include bridged rings or fused rings.

The term “heteroaryl” or “hetaryl” refers to a monovalent monocyclicand/or multicyclic aromatic group that contain at least one aromaticring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, N, and P in the ring, andwhich is bonded to the rest of the molecule through the aromatic ring,and may also be optionally substituted. Each ring of a heteroaryl groupcan contain one or two O atoms, one or two S atoms, one to four N atoms,and/or one to four P atoms, provided that the total number ofheteroatoms in each ring is four or less and each ring contains at leastone carbon atom. In certain embodiments, the heteroaryl has 5 to 20 ringatoms.

The term “alkylaryl” refers to an aryl group with an alkyl substituent.The term “arylalkyl” includes an alkyl group with an aryl substituent.

The term “alkylheterocyclyl” refers to a heterocyclyl group with analkyl substituent. The term “heterocyclylalkyl” includes an alkyl groupwith a heterocyclyl substituent.

The term “alkylheteroaryl” refers to a heteroaryl group with an alkylsubstituent. The term alkylheteroaryl includes an alkyl group with aheteroaryl substituent.

The term “acyl group”, “alkanoyl group”, or “aroyl group” as used hereinrefers to a chemical entity comprising the general formula R—C(═O)—where R represents any aliphatic, alicyclic, or aromatic group and C(═O)represents a carbonyl group.

The term “acylation” as used herein refers to any process whereby anacid, or an acid derivative such as an acid halide or an acid anhydrideis used to convert a hydroxyl group into an ester, or an amine into anamide.

“Halogen” or “halo” refers to fluoro, chloro, bromo or iodo; and theterm “halide” refers to fluoride, chloride, bromide and iodide.

The term of “phosphoramidate” as used herein refers to a phosphate thathas an NR₂ instead of an OH or OR group where R represents anyaliphatic, alicyclic, or aromatic group. In case of “phosphorodiamidate”two OHs or ORs are replaced with NR₂.

The terms of “phosphates” and “phosphate ester” as used herein refer toesters of phosphoric acid.

“Phosphonates” and “phosphonate esters” as used herein refer to estersof phosphonic acids containing C—P(═O)(OR)₂ groups where R is alkyl,aryl and the like.

The term of “phosphonamidate” as used herein refers to a phosphonatethat has an NR₂ instead of an OH or OR group where R represents anyaliphatic, alicyclic, or aromatic group. In case of “phosphonodiamidate”two OHs or ORs are replaced with NR₂.

The term “nucleoside” as used herein refers to a molecule composed of aheterocyclic nitrogenous base, particularly a purine or pyrimidine,containing an N-glycosidic linkage with a sugar, particularly a pentose.Nucleosides include both L- and D-nucleoside enantiomers.

The term “nucleoside analogue” as used herein refers to a non-naturalnucleoside, a “nucleoside” derivative, a “carbocyclic nucleoside”, a“C-nucleoside”, or an “acyclic nucleoside”.

The term “carbocyclic nucleoside” as used herein refers to a nucleosideor nucleoside analog containing a sugar-like moiety with 4′-oxodisplaced by methylene or substituted methylene or methine such ascyclopentanes, cyclobutanes and the like, which are not N-glycosides andinclude phosphorylation site(s) or phosphate, or phosphonate, or theirprecursors.

The term “C-nucleoside” as used herein refers to nucleosides in whichthe ribofuranosyl moiety is linked to a heterocyclic base through acarbon-to-carbon bond instead of the traditional carbon-to-nitrogenbond.

The term “acyclic nucleoside” as used herein refers to a nucleoside ornucleoside analog containing an alkyl as a sugar-like moiety, whichincludes phosphorylation site(s) or phosphate, or phosphonate, or theirprecursors. Examples related to this invention include, but not limitingto, ganciclovir, famciclovir, and cidofovir.

The term “pronucleotides” or “ProTides” as used herein refers tophosphorylated nucleoside analogues in which the phosphate moiety hasbeen masked by various chemical entities to increase hydrophobicity,bypass first phosphorylation, and to allow targeted delivery to diseasedtissues and selective inhibition of viral enzymes.

The term “nucleophile” as used herein refers to an electron-rich reagentthat is an electron pair donor (contains an unshared pair of electrons)and forms a new bond to a carbon atom. Nucleophiles can be anions orneutrally charged. Examples include, but are not limited to, carbanions,oxygen anions, halide anions, sulfur anions, nitrogen anions, nitrogenbases, alcohols, ammonia, water, and thiols.

The term “leaving group” as used herein refers to a weakly basicchemical entity that is readily released from carbon, and takes the pairof bonding electrons binding it with said carbon atom. Leaving groupsare chemical functional groups that can be displaced from carbon atomsby nucleophilic substitution. Examples include, but are not limited to,alkylsulfonates, substituted alkylsulfonates, arylsulfonates,substituted arylsulfonates, heterocyclicsulfonates,trichloroacetimidate, alkoxide, and aryloxide groups. Preferred leavinggroups include, but are not limited to, chloride, bromide, iodide,p-nitrobenzenesulfonate (nosylate),p-(2,4-dinitroanilino)benzenesulfonate, benzenesulfonate,methylsulfonate (mesylate), p-methylbenzenesulfonate (tosylate),p-bromobenzenesulfonate (brosylate), trifluoromethylsulfonate(triflate), 2,2,2-trifluoroethanesulfonate, imidazolesulfonate,trichloroacetimidate, trifluoroacetate and other acylates, alkoxide, andaryloxide, i.e., 4-nitrophenoxide, pentafluorophenoxide, and2,4,6-trichlorophenoxide.

The synonymous terms “hydroxyl protecting group” and “alcohol-protectinggroup” as used herein refer to substituents attached to the oxygen of analcohol group commonly employed to block or protect the alcoholfunctionality while reacting other functional groups on the compound.Examples of such alcohol-protecting groups include the2-tetrahydropyranyl group, 2-(bisacetoxyethoxy)methyl group, tritylgroup, trichloroacetyl group, carbonate-type blocking groups such asbenzyloxycarbonyl (Cbz), trialkylsilyl groups, examples of such beingtrimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl, estergroups such as formyl, (C₁-C₁₀) alkanoyl (optionally mono-, di- ortri-enriched with (C₁-C₆) alkyl, (C₁-C₆) alkoxy, halo, aryl, aryloxy orhaloaryloxy), and the like, the aroyl group (including optionally mono-,di- or tri-enriched on the ring carbons with halo, (C₁-C₆) alkyl,(C₁-C₆) alkoxy wherein aryl is phenyl, 2-furyl, and the like),carbonates, sulfonates, and ethers such as benzyl, p-methoxybenzyl,methoxymethyl, 2-ethoxyethyl, benzyloxymethyl (BOM) group, and etc. Thechoice of alcohol-protecting group employed is not critical so long asthe derivatized alcohol group is stable to the conditions of subsequentreaction(s) on other positions of the compound of the formula and can beremoved at the desired point without disrupting the remainder of themolecule. Further examples of groups referred to by the above terms aredescribed by J. W. Barton, “Protective Groups In Organic Chemistry”, J.G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and G. M. Wuts,T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley &Sons Inc., Hoboken, N.J., 2007, which are hereby incorporated byreference. The related terms “protected hydroxyl” or “protected alcohol”define a hydroxyl group substituted with a hydroxyl protecting group asdiscussed above.

The term “nitrogen protecting group,” as used herein, refers to groupsknown in the art that are readily introduced on to and removed from anitrogen atom. Examples of nitrogen protecting groups include acetyl(Ac), trifluoroacetyl, benzoyl (Bz), Boc, Cbz, trityl, DMTr, and benzyl(Bn). See also G. M. Wuts, T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley & Sons Inc., Hoboken, N.J., 2007, and relatedpublications.

The term “purine” or “pyrimidine” base refers to, but is not limited to,adenine, N⁶-alkyl adenines, N⁶-cycloalkyl adenines, N⁶-acyl adenines(wherein acyl is C(═O)(alkyl, aryl, alkylaryl, or arylalkyl),6-alkylaminopurine, 6-halopurine, 6-vinylpurine, 6-acetylenic purine,6-acyl purine, 6-alkoxyl purine, 6-aryloxyl purine, 6-alkylthio purine,2-akylaminopurines, 2-akylamino-6-oxopurine, 2-akylamino-6-thiopurines,2-heteroaryl purine, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,5-alkylpyrimidines, 5-benzylpyrimidines, 5-halopyrimidines,5-vinylpyrimidine, 5-acetylenic pyrimidine, 5-acyl pyrimidine,5-hydroxyalkyl pyrimidine, 5-amidopyrimidine, 5-cyanopyrimidine,5-iodopyrimidine, 6-iodo-pyrimidine, 5-bromovinyl pyrimidine,6-bromovinyl pyrimidine, 5-nitropyrimidine, 5-aminopyrimidine,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, andtriazolopyrimidinyl. Purine bases further include, but are not limitedto, guanine, hypoxanthine, 7-deazaguanine, 7-deazaadenine,4-aza-7,9-dideazaadenine, 2,6-diaminopurine, 6-amino-2-fluoropurine,6-amino-2-chloropurine, and 6-chloropurine. Functional oxygen andnitrogen groups on the base can be protected as necessary or desired.Suitable protecting groups are well known to those skilled in the art,and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl,and t-butyldiphenylsilyl, trityl, alkyl groups, dimethylformamidinegroup, and acyl groups such as acetyl, benzoyl, isobutyryl andpropionyl, methanesulfonyl, and p-toluenesulfonyl.

The term “amino acid” refers to naturally occurring and synthetic α-,β-, γ-, or δ-amino acids, and includes but is not limited to, naturalamino acids, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In certain embodiments, the amino acid is in theD- or L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-serinyl,β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl,β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl.

The compounds of this invention can contain one or more asymmetriccarbon or phosphorus atoms (chiral centers), so that the compounds canexist in different stereoisomeric forms such as racemic mixtures,diastereomeric mixtures, optically active non-racemic mixtures, orsingle enantiomers. The single enantiomers, i.e., in optically pureforms, can be obtained by asymmetric synthesis or by resolution ofracemic mixtures by conventional methods well-known to those skilled inthe art.

The term of “Solvate” refers to a compound provided herein or a saltthereof that further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate is a hydrate, where the solvent is water.

The term of “Isotopically enriched” refers to a compound containing atleast one atom having an isotopic composition other than the naturalisotopic composition of that atom. The term of “Isotopic composition”refers to the amount of each isotope present for a given atom, and“natural isotopic composition” refers to the naturally occurringisotopic composition or abundance for a given atom. As used herein, anisotopically enriched compound optionally contains deuterium, carbon-13,nitrogen-15, and/or oxygen-18 at amounts other than their naturalisotopic compositions.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment or preventionof a disorder or one or more symptoms thereof. In certain embodiments,the term “therapeutic agent” includes a compound provided herein. Incertain embodiments, a therapeutic agent is an agent known to be usefulfor, or which has been or is currently being used for the treatment orprevention of a disorder or one or more symptoms thereof.

The term of “Pharmaceutically acceptable salt” refers to any nontoxicsalt of a compound provided herein which retains the biologicalproperties of the compound and has no undesirable properties forpharmaceutical use. Such salts may be derived from a variety of organicand inorganic counter-ions well known in the art, and include, but arenot limited to: (1) acid addition salts formed when the compoundcontains one or more basic functionalities such as amine, purine, andpyrimidine, with organic or inorganic acids; or (2) salts formed when anacidic proton present in the parent compound such as carboxylic acid,phosphoric acid, and phosphonic acid, is either replaced by a metal ion,such as sodium, potassium, and ammonium, or coordinated with an organicbase, such as aliphatic, alicyclic, or aromatic organic amines. Itshould be understood that all references to pharmaceutically acceptablesalts include solvent addition forms (solvates) or crystal forms(polymorphs) as defined herein, of the same acid addition salt.

Compounds

An aspect of the invention is directed to a compound, itsisotope-enriched analogues, its salts, hydrates, solvates, crystallineforms, and the like represented by formula I:

wherein

(a) R is a moiety derivable by removal of 3′- and 5′-hydroxyl radicalsfrom a therapeutic nucleoside or its equivalents.

(b) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to represent a phosphonate or phosphonamidate;

(c) X₁ is O, S or Se;

(d) PR⁰ is selected as follows: (i) phosphate, or phosphoramidaterepresented by PY₄R² where Y₄ is O, S, Se, or NR^(8′″); (ii)phosphoramidate of amino acid esters or amides, or of esters or amidesof modified amino acids, represented byPY₁[C(R^(1a)R^(1b))]_(d)C(═X₂)Y₄R² where Y₁ is NR⁸, X₂ is O, S or Se,and Y₄ is O, S, Se, or NR^(8′″);

(e) M is a molecular bridge selected from CR^(5a)R^(5b),(CR^(5a)R^(5b))_(d)OC(═O), and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to4;

(f) Y₁, Y₂, Y₃, and Y₄ are selected as follows: (i) Y₁ is selected fromO, S, Se, and NR⁸; (ii) Y₂ is selected from O, S, Se, and NR^(8′); (iii)Y₃ is selected from O, S, Se, and NR^(8″); (iv) Y₄ is selected from O,S, Se, and NR^(8′″); (v) R⁸ and R^(1a) or R^(1b) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where n is 2 to 4, and Y₁ is NR⁸; (vi) R^(8′) and R^(5a) or R^(5b)together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4 and Y₂ is NR^(8′); (vii)R^(8″) and R^(5a) or R^(5b) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4, and Y₃ is NR^(8″); (viii) Y₃ is O, and Y₂ is NR^(8′), so thatY₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a natural or modifiedα-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S; (ix) the saidmodified α-amino acids can be a β-, γ-, or δ-amino acid or its analoguesrepresented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2 to 4; (x) Y₂can be O or S of an α-amino acid residue as in serine (OH), threonine(OH), and cysteine (SH), and the amino can be substituted orunsubstituted;

(g) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(h) R⁸, R^(8′), R^(8″), and R^(8′″) are independently selected fromhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸, R^(8′), R^(8″), or R^(8″) in Y_(x) can be the sameor different groups where x is 1 to 4;

(i) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl, heteroaryl, arylalkyl(C₁-C₃), andheteroarylalkyl(C₁-C₃), where c is 1 to 6, d is 0 to 2, e is 0 to 3, andsaid aryl groups are optionally substituted with a group selected fromhydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, andwhere R^(1′) is independently hydrogen or alkyl, which includes, but isnot limited to, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂;(ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH,CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂,CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph),CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b) is H and R^(1a)is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H,CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4 and Y₁ is NR⁸; (vii) R^(1b) is hydrogenand R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4 and Y₁ isNR⁸;

(j) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8′), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;

(k) The Y₂-M-Y₃ linker is represented as Y₂—(CR^(5a)R^(5b))-3′-Y₃, whereY₃ is O, S, or NR^(8″), forming a 8-membered ring fused with pentosesugar at 3′ and 5′-P or equivalent positions in acyclic and carbocyclicnucleoside analogues, or Y₂—(CR^(5a)R^(5b))_(d)C(═O)-3′-Y₃, orY₂—(CR^(5a)R^(5b))_(d)OC(═O)—Y—Y₃, or the like, and d is 1 to 4, forminga 9 to 12-membered ring.

As can be appreciated from the structure represented by formula I above,there are myriad ways to express the several embodiments and aspects ofeach embodiment of the present invention. As seen below, the inventorshave disclosed certain embodiments directed to the compound of formulaI, each having several aspects, based on the identity of molecularbridges. This is not intended to be an explicit or implicit admissionthat these embodiments are independent or distinct nor should it beinterpreted as such. Rather, it is intended to convey information sothat the full breadth of the present invention can be understood.Furthermore, the following embodiments, and aspects thereof, are notmeant to be limiting on the full breadth of the invention as recited bythe structure of formula I.

A first embodiment of the invention is directed to a compoundrepresented by formula I-1:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, aryl, and heteroaryl; (ii) CR^(7a)R^(7b) isC(CH₂)_(m) so as to form a spiro ring where m is 2 to 5, or is asubstituted or unsubstituted spiro epoxide, aziridine, or oxetane; (iii)R⁴ is CH₂ so as to form a substituted bicyclo[3.1.0]hexane includingA₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to represent a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) PR⁰ is selected as follows: (i) phosphate, or phosphoramidaterepresented by PY₄R² where Y₄ is O, S, Se, or NR^(8′″); (ii)phosphoramidate of amino acid esters or amides, or of esters or amidesof modified amino acids, represented byPY₁[C(R^(1a)R^(1b))]_(d)C(═X₂)Y₄R² where Y₁ is NR⁸, X₂ is O, S or Se,and Y₄ is O, S, Se, or NR^(8′″);

(i) X₁ is O, S or Se;

(j) M is a molecular bridge selected from CR^(5a)R^(5b),(CR^(5a)R^(5b))_(d)OC(═O), and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to4;

(k) Y₁, Y₂, Y₃, and Y₄ are selected as follows: (i) Y₁ is selected fromO, S, Se, and NR⁸; (ii) Y₂ is selected from O, S, Se, and NR^(8′); (iii)Y₃ is selected from O, S, Se, and NR^(8″); (iv) Y₄ is selected from O,S, Se, and NR^(8′″); (v) R⁸ and R^(1a) or R^(1b) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where n is 2 to 4, and Y₁ is NR⁸; (vi) R^(8′) and R^(5a) or R^(5b)together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4 and Y₂ is NR^(8′); (vii)R^(8″) and R^(5a) or R^(5b) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4, and Y₃ is NR^(8″); (viii) Y₃ is O, and Y₂ is NR^(8′), so thatY₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a natural or modifiedα-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S; (ix) the saidmodified α-amino acids can be a β-, γ-, or δ-amino acid or its analoguesrepresented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2 to 4; (x) Y₂can be O or S of an α-amino acid residue as in serine (OH), threonine(OH), and cysteine (SH), and the amino can be substituted orunsubstituted;

(l) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(m) R⁸, R^(8′), R^(8″), and R^(8′″) are independently selected fromhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸, R^(8′), R^(8″), or R^(8″) in Y_(x) can be the sameor different groups where x is 1 to 4;

(n) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(c)COR^(1″), aryl, heteroaryl, arylalkyl(C₁-C₃), andheteroarylalkyl(C₁-C₃), where c is 1 to 6, d is 0 to 2, e is 0 to 3, andsaid aryl groups are optionally substituted with a group selected fromhydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, andwhere R¹ is independently hydrogen or alkyl, which includes, but is notlimited to, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii)R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH,CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂,CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph),CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b) is H and R^(1a)is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H,CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4 and Y₁ is NR⁸; (vii) R^(1b) is hydrogenand R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4 and Y₁ isNR⁸;

(o) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8′), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;

(p) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base represented by, but notlimited to, the following structures:

wherein

(i) Z is N or CR¹⁶;

(ii) R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are independently H, F, Cl, Br,I, OH, OR′, SH, SR′, SeH, SeR′, NH₂, NHR′, NR′₂, NHNH₂, NR′NH₂, NR′NHR′,NHNR′₂, NR′NR′₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) loweralkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H,or CH═CHCO₂R′, wherein R′ is an optionally substituted alkyl, whichincludes, but is not limited to, an optionally substituted C₁-C₂₀ alkyl,an optionally substituted lower alkyl, an optionally substitutedcycloalkyl, an optionally substituted alkynyl of C₂-C₆, an optionallysubstituted lower alkenyl of C₂-C₆, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted sulfonyl,or optionally substituted acyl, which includes but is not limited toC(═O) alkyl, or alternatively, in the instance of NR′₂, each R′ compriseat least one C atom that are joined to form a heterocycle comprising atleast two carbon atoms;

(iii) Y₅ is selected from O, S, and Se;

(iv) R¹⁶ is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, NO₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) loweralkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, C(═O)NH₂, C(═O)NHR′, C(═O)NR′₂,CH═CHCO₂H, or CH═CHCO₂R′, aryl, or heteroaryl.

A second embodiment of the invention is directed to a compoundrepresented by formula I-2:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) soas to form a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, or C₁-C₆ alkyl, aryl, whereA₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to form a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) X₁ and X₂ are independently selected from O, S or Se;

(i) M is a molecular bridge selected from CR^(5a)R^(5b),(CR^(5a)R^(5b))_(d)OC(═O), and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to4;

(j) Y₁, Y₂, Y₃, and Y₄ are selected as follows: (i) Y₁ is selected fromO, S, Se, and NR⁸; (ii) Y₂ is selected from O, S, Se, and NR^(8′); (iii)Y₃ is selected from O, S, Se, and NR^(8″); (iv) Y₄ is selected from O,S, Se, and NR^(8′″); (v) R⁸ and R^(1a) or R^(1b) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where n is 2 to 4, and Y₁ is NR⁸; (vi) R^(8′) and R^(5a) or R^(5b)together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4 and Y₂ is NR^(8′); (vii)R^(8″) and R^(5a) or R^(5b) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4, and Y₃ is NR^(8″); (viii) Y₃ is O, and Y₂ is NR^(8′), so thatY₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a natural or modifiedα-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S; (ix) the saidmodified α-amino acids can be a β-, γ-, or δ-amino acid or its analoguesrepresented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2 to 4; (x) Y₂can be O or S of an α-amino acid residue as in serine (OH), threonine(OH), and cysteine (SH), and the amino can be substituted orunsubstituted;

(k) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(l) R⁸, R^(8′), R^(8″), and R^(8′″) are independently selected fromhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸, R^(8′), R^(8″), or R^(8′″) in Y_(x) can be the sameor different groups where x is 1 to 4;

(m) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl, heteroaryl, arylalkyl(C₁-C₃), andheteroarylalkyl(C₁-C₃), where c is 1 to 6, d is 0 to 2, e is 0 to 3, andsaid aryl groups are optionally substituted with a group selected fromhydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, andwhere R^(1′) is independently hydrogen or alkyl, which includes, but isnot limited to, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂;(ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH,CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂,CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph),CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b) is H and R^(1a)is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H,CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4 and Y₁ is NR⁸; (vii) R^(1b) is hydrogenand R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4 and Y₁ isNR⁸;

(n) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8′), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;

(o) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A third embodiment of the invention is directed to a compoundrepresented by formula I-3:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) soas to form a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to form a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) X₁ is selected from O, S or Se;

(i) M is a molecular bridge selected from CR^(5a)R^(5b),(CR^(5a)R^(5b))_(d)OC(═O), and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to4;

(j) Y₂, Y₃, and Y₄ are selected as follows: (i) Y₂ is selected from O,S, Se, and NR^(8′); (ii) Y₃ is selected from O, S, Se, and NR^(8″);(iii) Y₄ is selected from O, S, Se, and NR^(8′″); (iv) R^(8′) and R^(5′)or R^(5b) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms, where n is 2 to 4 and Y₂ isNR^(8′); (v) R^(8″) and R^(5a) or R^(5b) together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4, and Y₃ is NR^(8″); (vi) Y₃ is O, and Y₂ is NR^(8′), so thatY₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a natural or modifiedα-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S; (vii) thesaid modified α-amino acids can be a β-, γ-, or δ-amino acid or itsanalogues represented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2 to 4;(viii) Y₂ can be O or S of an α-amino acid residue as in serine (OH),threonine (OH), and cysteine (SH), and the amino can be substituted orunsubstituted;

(k) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(l) R^(8′), R^(8″), and R^(8′″) are independently selected fromhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R^(8′), R^(8″), or R^(8″) in Y_(x) can be the same ordifferent groups where x is 2 to 4;

(m) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8″), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;

(n) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A fourth embodiment of the invention is directed to a compoundrepresented by formula I-2-1:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) soas to form a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(f) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R¹ is independently hydrogen or alkyl, whichincludes, but is not limited to, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or—N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃,CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b)is H and R^(1a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4; (vii) R^(1b) is hydrogen and R^(1a) andR⁸ together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4;

(g) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(h) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(i) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(j) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A fifth embodiment of the invention is directed to a compoundrepresented by formula I-2-2:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) independently selected from areH, alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) so as to form aspiro ring where m is 2 to 5, or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ so as to form asubstituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(f) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or alkyl,which includes, but is not limited to, C₁-C₂₀ alkyl, and R^(1″) is—OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b)is H and R^(1a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4; (vii) R^(1b) is hydrogen and R^(1a) andR⁸ together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4;

(g) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(h) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(i) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(j) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A sixth embodiment of the invention is directed to a compoundrepresented by formula I-2-3:

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) soas to form a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(g) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(h) R⁸ and R^(8′) are independently selected from hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ alkyl optionally substituted with a lower alkyl,alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸ and R^(8′) can be the same or different groups;

(i) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxyl (C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or alkyl,which includes, but is not limited to, C₁-C₂₀ alkyl, and R^(1″) is—OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b)is H and R^(1a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) and R⁸ together are (CH₂)_(m) so as to form a spiroring, where m is 2 to 5; (vi) R^(1a) is hydrogen, and R^(1b) and R⁸together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4; (vii) R^(1b) is hydrogen,and R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4;

(j) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen, andR^(5b) and R^(8′) together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms where n is 2 to 4; (v) R^(5b)is hydrogen, and R^(5a) and R^(8′) together are (CH₂)_(n) so as to forma cyclic ring that includes the adjoining N and C atoms, where n is 2 to4;

(k) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A seventh embodiment of the invention is directed to a compoundrepresented by formula I-2-4:

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino, and R^(7a) and R^(7b) are independently selected fromH, OH, SH, F, Cl, alkyl, aryl, and heteroaryl; (ii) CR^(7a)R^(7b) isC(CH₂)_(m) so as to form a spiro ring where m is 2 to 5, or is asubstituted or unsubstituted spiro epoxide, aziridine, or oxetane; (iii)R⁴ is CH₂ so as to form a substituted bicyclo[3.1.0]hexane includingA₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, OH,alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(g) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(h) R⁸ and R^(8′) are independently selected from hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ alkyl optionally substituted with a lower alkyl,alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸ and R^(8′) can be the same or different groups;

(i) R^(1a) and R^(1b) are selected as follows: (i) R^(1a) and R^(1b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)NR^(1′) ₂, hydroxyl (C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R¹ is independently hydrogen or alkyl, whichincludes, but is not limited to, C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or—N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃,CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b)is H and R^(1a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4; (vii) R^(1b) is hydrogen and R^(1a) andR⁸ together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where n is 2 to 4;

(j) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where n is 2 to 4; (v) R^(5b) ishydrogen and R^(5a) and R^(8′) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4;

(k) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A seventh embodiment of the invention is directed to a compoundrepresented by formula I-3-1:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino, andR^(7a) and R^(7b) are independently selected from H, OH, SH, F, Cl,alkyl, aryl, and heteroaryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) so as toform a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, OH, alkyl, aryl, heteroaryl,alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, orheteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to represent a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(i) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(j) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(k) X₁ is O, S or Se;

(l) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(m) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

An eighth embodiment of the invention is directed to a compoundrepresented by formula I-3-2:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino, andR^(7a) and R^(7b) are independently selected from H, OH, SH, F, Cl,alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) so as to form a spiroring where m is 2 to 5, or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ so as to form asubstituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isR^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, heteroaryl, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to form a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(i) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(j) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(k) X₁ is O, S or Se;

(1) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(m) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A ninth embodiment of the invention is directed to a compoundrepresented by formula I-3-3:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino, andR^(7a) and R^(7b) are independently selected from H, OH, SH, F, Cl,alkyl, aryl, and heteroaryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) so as toform a spiro ring where m is 2 to 5, or is a substituted orunsubstituted spiro epoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ soas to form a substituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isH, OH, alkyl, aryl, heteroaryl, or COR^(6′) where R^(6′) is H, alkyl,aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino,or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to represent a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(i) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(j) R^(8′) and R^(8′″) are independently selected from hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ alkyl optionally substituted with a lower alkyl,alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸ and R^(8′) can be the same or different groups;

(k) X₁ is O, S or Se;

(l) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where n is 2 to 4; (v) R^(5b) ishydrogen and R^(5a) and R^(8′) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4;

(m) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A tenth embodiment of the invention is directed to a compoundrepresented by formula I-3-4:

wherein

(a) A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b), where(i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, or heteroarylamino, andR^(7a) and R^(7b) are independently selected from H, OH, SH, F, Cl,alkyl, and aryl; (ii) CR^(7a)R^(7b) is C(CH₂)_(m) so as to form a spiroring where m is 2 to 5, or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane; (iii) R⁴ is CH₂ so as to form asubstituted bicyclo[3.1.0]hexane including A₁CR⁴;

(b) A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane;

(c) W is H, F, halogen, OH, OMe, NHR⁶ or N₃ where A₂R³ is CR³, and R⁶ isH, OH, alkyl, aryl, heteroaryl, or COR^(6′) where R^(6′) is H, alkyl,aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino,or heteroarylamino;

(d) R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl orheteroaryl, where A₂W is CW;

(e) R^(3′) is H, CH₃, CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxycarbonyl, or thioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀alkylaminocarbonyl), arylcarbamoyl, or heteroarylcarbamoyl;

(f) A₃ is selected as follows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H,OR^(6′), alkyl, aryl, COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl,aryl, or heteroaryl; (ii) A₃CH₂ can be optionally replaced with CH₂A₃,or CF₂A₃, so as to form a phosphonate or phosphonamidate;

(g) L and R⁴ are independently selected from H, a lower alkyl, CN,vinyl, O-(lower alkyl), hydroxyl lower alkyl (i.e., —(CH₂)_(p)OH, wherep is 1 to 6, including hydroxyl methyl (CH₂OH)), CH₂F, N₃, CH₂CN,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl (optionally substituted), orhalogen, including F, Cl, Br, or I;

(h) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(i) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(j) R^(8′) and R^(8′″) are independently selected from hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ alkyl optionally substituted with a lower alkyl,alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, substituted heteroaryl,OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, andheteroarylamino; R⁸ and R^(8′) can be the same or different groups;

(k) X₁ is O, S or Se;

(l) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a Spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where n is 2 to 4; (v) R^(5b) ishydrogen and R^(5a) and R^(8′) together are (CH₂)_(n) so as to form acyclic ring that includes the adjoining N and C atoms, where n is 2 to4;

(m) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

An eleventh embodiment of the invention is directed to a compoundrepresented by formula I-2-1-1:

wherein

(a) (i) R^(1a) and R^(1b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)NR^(1′) ₂, hydroxyl (C₁-C₆)alkyl,—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R^(1′) isindependently hydrogen or alkyl, which includes, but is not limited to,C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is Hand R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(C0H₂)_(m) so as to form a spiro ring; (vi) R^(1a) is hydrogen andR^(1b) and R⁸ together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms, where n is 2 to 4; (vii) R^(1b) ishydrogen and R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4;

(b) (i) R^(5a), R^(5b) are independently selected from hydrogen, C₁-C₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH,—(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR¹, aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R^(1′) isindependently hydrogen or C₁-C₆ alkyl and R^(1″) is —OR^(1′) or—N(R^(1′))₂; (ii) R^(5a) and R^(5b) both are C₁-C₆ alkyl; (iii) R^(5a)and R^(5b) together are (CH₂)_(m) so as to form a spiro ring, where m is2 to 5;

(c) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(d) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A twelfth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2:

wherein

(a) (i) R^(1a) and R^(1b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(x)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl,—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R¹ isindependently hydrogen or alkyl, which includes, but is not limited to,C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is Hand R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(CH₂)_(m) so as to form a spiro ring, where m is 2 to 5; (vi) R^(1a) ishydrogen and R^(1b) and R⁸ together are (CH₂)_(n) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4; (vii)R^(1b) is hydrogen and R^(1a) and R⁸ together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4;

(b) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(c) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(d) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A thirteenth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-3:

wherein

(a) (i) R^(1a) and R^(1b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl,—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R¹ isindependently hydrogen or alkyl, which includes, but is not limited to,C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is Hand R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(CH₂)_(m) so as to form a spiro ring, where m is 2 to 5; (vi) R^(1a) ishydrogen and R^(1b) and R⁸ together are (CH₂)_(n) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4; (vii)R^(1b) is hydrogen and R^(1a) and R⁸ together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4;

(b) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(c) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(d) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A fourteenth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-4:

wherein

(a) (i) R^(1a) and R^(1b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl,—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(c)COR^(1″), aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R¹ isindependently hydrogen or alkyl, which includes, but is not limited to,C₁-C₂₀ alkyl, and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is Hand R^(1b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(CH₂)_(m) so as to form a spiro ring, where m is 2 to 5; (vi) R^(1a) ishydrogen and R^(1b) and R⁸ together are (CH₂)_(n) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4; (vii)R^(1b) is hydrogen and R^(1a) and R⁸ together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4;

(b) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(c) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(d) R⁸ is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl,substituted heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, and heteroarylamino;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A fifteenth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1:

wherein

(a) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(b) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(c) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(d) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A sixteenth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-2:

wherein

(a) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(b) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(c) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(d) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A seventeenth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-3:

wherein

(a) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(b) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(c) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(d) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

An eighteenth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-4:

wherein

(a) Y₄ is O, S, Se, or NR^(8′″) where R^(8′″) is hydrogen, alkyl, oraryl as defined below;

(b) R² is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, andsubstituted heteroaryl;

(c) R^(8′″) is selected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyloptionally substituted with a lower alkyl, alkoxyalkyl, di(loweralkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aryl such as phenyl, heteroaryl such aspyridinyl, substituted aryl, substituted heteroaryl, OH, alkoxy,aryloxy, heteroaryloxy, alkylamino, arylamino, and heteroarylamino;

(d) R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5;

(e) Q is any nucleic acid base and analogues, either a naturallyoccurring or modified purine or pyrimidine base.

A nineteenth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2a:

A twentieth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2b:

A twenty first embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2c:

A twenty second embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2d:

A twenty-third embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2e:

A twenty-fourth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2f:

A twenty-fifth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2g:

A twenty-sixth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2h:

A twenty-seventh embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2i:

A twenty-eighth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2j:

A twenty-ninth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2k:

A thirtieth embodiment of the invention is directed to a compoundrepresented by formula I-2-1-2l:

A thirty-first embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1a:

A thirty-second embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1b:

A thirty-third embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1c:

A thirty-fourth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1d:

A thirty-fifth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1e:

A thirty-sixth embodiment of the invention is directed to a compoundrepresented by formula I-3-1-1f:

In other embodiments, non-limiting examples of nucleosides that can bederivatized to bc-ProTides shown in Formula I-1 include:

Process for Preparation of Compounds

Another embodiment of this invention represents processes forpreparation of these compounds provided herein, which can also beprepared by any other methods apparent to those skilled in the art.Exemplary methods are provided in Scheme I to VII.

In certain embodiments, the compounds provided herein can be prepared byintermolecular cyclization by alkylation, acetal formation, ketalformation, and etc. as provided in Scheme I, wherein Lg¹ and Lg² areleaving groups selected from alkoxyl, halogen, sulfate, and otherleaving groups apparent to those skilled in the art. One or moreprotection steps may be included in the method provided in scheme I.

In certain embodiments, the compounds provided herein can be prepared bystepwise intermolecular cyclization via an activation step as providedin Scheme II. Lg can be halogen, or OH, which can be activated as aleaving group by activating agents such as DCC, EDCI, HATU, and others,or known to those of skill in art. Nu¹ is OH, SH, or NHR^(8′). Lg² canbe alkylthio and arylthio which can be activated to correspondingsulfates (Lg^(2′)). One or more protection and deprotection steps may beincluded in the method provided in scheme II.

In certain embodiments, the compounds provided herein can be prepared bystepwise intermolecular cyclization via an activation step as providedin Scheme III. Lg¹ can be halogen, or OH, which can be activated as aleaving group by activating agents such as sulfonyl halides, and othersknown to those skilled in the art. Y₂ can be O, S, or NHR^(8′). Y₃ canbe O, S, or NHR^(8″). Lg can be alkylthio and arylthio which can beactivated to corresponding sulfates (Lg^(2′)). One or more protectionand deprotection steps may be included in the method provided in schemeIII.

In certain embodiments, the compounds provided herein can be prepared bystepwise intermolecular cyclization via an activation step as providedin Scheme IV. Lg⁴ can be halogen, or OH, which can be activated as aleaving group such as mesylate, tosylate, triflate and others known tothose skilled in the art. Lg² can be alkylthio and arylthio which can beactivated to corresponding sulfates (Lg^(2′)). One or more protectionand deprotection steps may be included in the method provided in schemeIV.

In certain embodiments, the compounds provided herein can be prepared bystepwise intermolecular cyclization via an activation step as providedin Scheme V. Lg³ can be halogen, or OH, which can be activated as aleaving group by activating agents such as DCC, EDCI, HATU, and othersknown to those of skill in the art. Lg² can be alkylthio and arylthiowhich can be activated to corresponding sulfates (Lg^(2′)). One or moreprotection and deprotection steps may be included in the method providedin scheme V.

In certain embodiments, the compounds provided herein can be prepared bystepwise intermolecular cyclization via an activation step as providedin Scheme VI. Lg³ can be halogen. Lg² can be alkoxyl or OH, which can beactivated by reagents such as DCC, EDCI, HATU, and others to a leavinggroup Lg^(2′) known to those of skill in the art. One or more protectionand deprotection steps may be included in the method provided in schemeVI.

In certain embodiments, the compounds provided herein can be prepared byintermolecular cyclization as provided in Scheme VII. Lg² and Lg³ can behalogen.

EXAMPLES

The following examples further illustrate embodiments of the disclosedinvention, which are not limited by these examples.

Example 1 Compound 1 Preparation of (2S)-isopropyl2-(((6aR,8R,9R,9aR)-8-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-9-fluoro-9-methyl-4-oxidotetrahydro-6H-furo[3,2-f][1,3,5,2]trioxaphosphocin-4-yl)amino)propanoate(Scheme 1-A to C)

Method A (Scheme 1-A):

Preparation of Intermediate 1-1

In a round bottom flask, disodium p-nitrophenyl phosphate hexahydrate(0.5 mmol, 1 mol/eq) and isopropyl L-valinate hydrochloride (3 mol/eq)are dissolved in a mixture of tert-butanol (9 ml) and H₂O (2 ml). A fewdrops of triethylamine (Et₃N) are added to the solution to facilitatedissolution. An appropriate amount of N,N′-dicyclohexylcarbodiimide(DCC) (3 mol/eq) is dissolved in 1 ml of tert-butanol and is dropwiseadded to the reaction mixture. The reaction mixture is refluxedcarefully for 3-4 h while stirring. The progress of the reaction ismonitored by TLC (i-PrOH:NH₃:H₂O). Upon completion, the reaction mixtureis cooled down and the solvent is removed by rotary evaporation. Theproduct is isolated by silica column chromatography to affordintermediate 1-1.

Preparation of Intermediate 1-2

To a solution of intermediate 1-1 (0.5 mmol, 1 mol/eq) in DMF (20 mL) isadded chloromethyl methyl sulfide (1.1 mol/eq). The reaction mixture isstirred at 25° C. under N₂ for 1h. The solution is diluted with EtOAc(50 mL) and aqueous HCl solution (1%, 40 mL). The organic layer isseparated and washed with H₂O (50 mL). Then, it is dried over anhydrousMgSO₄, and concentrated under reduced pressure. Purification by silicagel column chromatography (EtOAc/MeOH) affords intermediate 1-2.

Method B (Scheme 1-B):

Preparation of Intermediate 1-3

To a stirred solution of p-nitrophenyl dichlorophosphate (1.00 mol/eq)and isopropyl valinate hydrochloride (1.00 mol/eq) in anhydrous DCM isadded, dropwise at −78° C. under an argon atmosphere, anhydrous TEA(2.00 mol/eq). Following the addition the reaction mixture is stirred at−78° C. for 1 h, then at room temperature for 2 h. Formation of thedesired compound is monitored by ³¹P NMR. After this period the solventis removed under reduced pressure and the residue is extracted with drydiethyl ether. The precipitate is filtered under nitrogen and thesolution is concentrated to give an oil, which is purified by flashcolumn chromatography (eluting with ethyl acetate/hexanes, 60/40) togive intermediate 1-3.

Preparation of Intermediate 1-1′

To a stirred solution of intermediate 1-3 (1.00 mol/eq) in anhydrousEt₂O is added, dropwise at 0° C., 1M tetrabutylammonium hydroxide in H₂O(2.00 mol/eq). The reaction mixture is stirred at 0° C. for 1.5 h.Formation of the desired compound is monitored by ³¹P NMR. After thisperiod the solvent is removed under reduced pressure and the residue isused for next step.

Preparation of Intermediate 1-2

To a solution of crude intermediate 1-1 or 1-1′ (0.5 mmol, 1 mol/eq) inDMF (20 mL) is added chloromethyl methyl sulfide (1.1 mol/eq). Thereaction mixture is stirred at 25° C. under N₂ for 1h. The solution isdiluted with EtOAc (50 mL) and aqueous HCl solution (1%, 40 mL). Theorganic layer is separated and washed with H₂O (50 mL). Then, it isdried over anhydrous MgSO₄, and concentrated under reduced pressure.Purification by silica gel column chromatography (EtOAc/MeOH, 6:4)affords intermediate 1-2.

Preparation of Intermediate 1-5

To a solution of1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione(0.5 mmol, 1 mol/eq) in anhydrous THF (1.5 mL) is added 1.0 M t-butylmagnesium chloride (1.05 mmol, 2.1 mol/eq) at rt. The resulting mixtureis stirred at rt for 0.5 h, and intermediate 1-2 (1.0 mmol) in THF (1.5mL) is added dropwise. The reaction mixture is stirred for 2 h, and thenquenched by adding saturated aqueous ammonium chloride (20 mL), andextracted twice with EtOAc (20 mL×2). The organic layers are combined,dried from MgSO₄, and concentrated till dryness to give a residue, whichis separated by silica gel chromatography to give intermediate 1-5.

Alternatively 3′-OH can be transiently protected by Cbz, and thendeprotected before oxidation/cyclization by hydrogenation.

Preparation of Compound 1

Condition A: Intermediate 1-5 (10 mmol, 1.0 mol/eq) is dissolved inanhydrous dichloromethane (200 mL) containing triethylamine (2.2 mol/eq)at room temperature, and then predried molecular sieves (3 Å) is added.The mixture is stirred in an ice-bath. A solution of sulfuryl chloride(1 mol/eq) in anhydrous dichloromethane is added dropwise to thereaction mixture during 30 minutes. The ice-bath is removed and thereaction mixture is stirred further till completion as shown by TLCanalysis. The solid is removed by filtration, and the filtrate is washedwith saturated aqueous sodium bicarbonate solution, followed by brine,and then dried over Na₂SO₄, filtered, concentrated. The obtained crudemixture is purified by silica gel column chromatography to give thecompound 1.

Condition B: Intermediate 1-5 (10 mmol, 1.0 mol/eq) is dissolved inanhydrous 1,2-dichloroethane (200 mL) containing triethylamine (2.2mol/eq). The solution is cooled in an ice-bath. Under N₂ atmosphere,bromine (1.1 eq.) is added very slowly. Stirring is continued at roomtemperature for additional 1 h. The reaction mixture is poured slowlyinto saturated aqueous sodium bicarbonate solution (50 mL) andseparated. The organic phase is washed with water (3×100 mL), brine (100mL) and dried over Na₂SO₄, filtered, concentrated. The obtained crudemixture is purified by silica gel column chromatography to give compound1.

Condition C: To a cooled mixture of thoroughly dried intermediate 1-5(5.00 mmol) and powdered 5 Å molecular sieves (˜200 mg) in anhydrous1,2-dichloroethane (DCE, 50 mL) at 0° C. is added a freshly preparedsolution of N-iodosuccinimide (NIS, 1.12 g, 5.00 mmol) and freshtrifluoromethanesulfonic acid (TfOH, 64 μL, 0.72 mmol) in DCE/Et₂O (1:1v/v, 25 mL). The addition of more TfOH (1 or 2×0.72 mmol) may benecessary to complete the reaction. After filtration of the suspension,the filtrate is diluted with CH₂Cl₂ (150 mL) and washed, sequentially,with aqueous 1 M sodium bisulfite (100 mL) and a saturated aqueoussolution of NaHCO₃ (100 mL). The organic layer is dried over anhydrousNa₂SO₄ and then filtered. The filtrate is evaporated till dryness togive a residue, and is purified by silica gel column chromatography togive compound 1.

Example 2 Compound 2 Preparation of isopropyl2-(((6aR,8R,9R,9aR)-8-(6-amino-9H-purin-9-yl)-9-hydroxy-9-methyl-4-oxidotetrahydro-6H-furo[3,2-f][1,3,5,2]trioxaphosphocin-4-yl)amino)propanoate(Scheme 2-A and B)

Method A:

Preparation of Intermediate 2-1

In a dry flask, toN-(9-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-9H-purin-6-yl)benzamide(1 mmol, 1 mol/eq) in anhydrous DMF (5 mL) stirred at 0° C. undernitrogen is added di-t-butylsilyl ditriflate (1.1 mol/eq) dropwise. Theresulting mixture is stirred at the same temperature till completion asshowed by TLC analysis. The reaction is diluted with EtOAc (50 mL), andwashed with H₂O (50 mL×3). Then, it is dried over anhydrous MgSO₄, andconcentrated under reduced pressure. Purification by silica gel columnchromatography (DCM/MeOH) affords intermediate 2-1.

Preparation of Intermediate 2-2

In a dry flask, intermediate 2-1 (1 mmol, 1 mol/eq) is dissolved in DCM(10 mL), and then DIPEA (1.4 mol/eq), catalytic amount oftetra-t-butylammonium iodide (0.05 mol/eq), and benzyloxymethyl chloride(1.2 mol/eq) are added. The reaction is stirred under reflux tillcompletion as showed by TLC analysis. The reaction is then cooled to−15° C. (HF)x.pyridine (3.7 mmol) (diluted (6 x) in pyridine at 0° C.)is slowly added. The reaction is stirred under nitrogen till completionas showed by TLC analysis. Volatiles are evaporated under vacuum to givea residue. Purification by silica gel column chromatography (DCM/MeOH)affords intermediate 2-2.

Preparation of Intermediate 2-3

To a solution of intermediate 2-2 (1 mmol, 1 mol/eq) in trimethylphosphate (3 mL) at 0° C. under nitrogen is added dropwise P(O)Cl₃ (2mol/eq). The mixture is stirred at this temperature till near completionas indicated by TLC analysis (i-PrOH/H₂O/NH₃—H₂O, 6:3:1). The reactionis quenched by addition of 0.2 M triethylammonium bicarbonate buffer (pH7.5, 10 mL). The resulting solution is stirred at 0° C. for 1 h, thenwarmed up to rt, and washed with EtOAc (×3). The aqueous solution islyophilized till dryness to give intermediate 2-3 as a slightly coloredfoam.

Preparation of Intermediate 2-4

In a two neck flask, intermediate 2-3 (1 mol/eq) and isopropylL-valinate hydrochloride (3 mol/eq) are dissolved in a mixture oftert-butanol (9 ml) and H₂O (2 ml). A few drops of triethylamine (Et₃N)are added to the solution to facilitate dissolution. An appropriateamount of N,N′-dicyclohexylcarbodiimide (DCC) (3 mol/eq) is dissolved in1 ml of tert-butanol and is dropwise added to the reaction mixture. Thereaction mixture is refluxed while stirring. The progress of thereaction is monitored by TLC (i-PrOH:NH₃:H₂O). Upon completion, thereaction mixture is cooled down and the solvent is removed by rotaryevaporation. The product is isolated by silica column chromatography toafford intermediate 2-4.

Preparation of Intermediate 2-5

To a solution of intermediate 2-4 (0.5 mmol, 1 mol/eq) in DMF (100 mL)are added potassium carbonate (15 mmol, 30 mol/eq) and dibromomethane(7.2 mmol, 14.4 mol/eq), and the resulting solution is stirred at rt for15 h. After removing the volatiles under reduced pressure, the residueis dissolved in DCM, and washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layers is then dried fromanhydrous magnesium sulfate, and concentrated till dryness to give aresidue, which is separated by a silica gel column to give intermediate2-5.

Preparation of Compound 2

Intermediate 2-5 (0.1 mmol, 1 mol/eq) is dissolved in EtOAc-EtOH (1:1,50 mL) in a dried flask, 10% wet palladium-carbon is then added. Themixture is purged with nitrogen twice, and hydrogenated (with a balloonfilled with H₂) at ambient temperature. After completion (monitored byTLC analysis), the solid is removed by filtration over a Celite layer.The filtrate is concentrated by evaporation under vacuum to provide thecrude product. Column chromatography on silica gel (MeOH/DCM) affordscompound 2.

Method B:

Preparation of Intermediate 2-6

In a dry flask, to(2R,3R,4R,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol(1 mmol, 1 mol/eq) in anhydrous DMF (5 mL) stirred at 0° C. undernitrogen is added di-t-butylsilyl ditriflate (1.1 mol/eq) dropwise. Theresulting mixture is stirred at the same temperature till completion asshown by TLC analysis. To the reaction is added imidazole (5 mol/eq) at0° C., and the resulting mixture is stirred for additional 5 min, andthen warmed up to rt. TBSCl (1.2 mol/eq) is added, the reaction is thenstirred at 60° C. under nitrogen till completion as shown by TLCanalysis. The reaction is diluted with EtOAc (50 mL) and H₂O (50 mL).The organic layer is collected and washed with H₂O (50 mL×2). Then, itis dried over anhydrous MgSO₄, and concentrated under reduced pressure.Purification by silica gel column chromatography (DCM/MeOH) affordsintermediate 2-6.

Preparation of Intermediate 2-7

Intermediate 2-6 is selectively deprotected at 3′ and 5′ by treatmentwith (HF)_(x).pyridine. Intermediate 2-6 (0.74 mmol, 1 mol/eq) isdissolved in DCM, and stirred at −15° C. (HF)_(x).pyridine (3.7 mmol, 5mol/eq) diluted (6 x) in pyridine at 0° C. is slowly added. The reactionis stirred under nitrogen till completion as shown by TLC analysis. Thereaction mixture is diluted by addition of DCM (50 mL), washed with H₂O(50 mL). Then, it is dried over anhydrous MgSO₄, and concentrated underreduced pressure. Purification by silica gel column chromatography(DCM/MeOH) affords intermediate 2-7.

Preparation of Intermediate 2-8

To a solution of intermediate 2-7 (1 mmol, 1 mol/eq) in trimethylphosphate (3 mL) at 0° C. under nitrogen is added dropwise P(O)Cl₃ (2mol/eq). The mixture is stirred at this temperature till near completionas indicated by TLC analysis (i-PrOH/H₂O/NH₃—H₂O, 6:3:1). To thismixture is then added L-valanyl isopropyl ester hydrochloride (1.5mol/eq) in CH₃CN (4 mL), followed by addition of DIPEA (10 mol/eq). Thereaction is stirred at 0° C. and then at rt for 1 h. Water (0.6 mL) isadded, and the reaction mixture is stirred for another 15 min. Thereaction is concentrated till dryness as a residue.

The above residue is dissolved in DMF (10 mL) is added chloromethylmethyl sulfide (1.1 mol/eq) and DIPEA (7 mol/eq). The reaction mixtureis stirred at 25° C. under N₂ for 1h. The solution is diluted with EtOAc(50 mL) and aqueous HCl solution (1%, 40 mL). The organic layer isseparated and washed with H₂O (50 mL). Then, it is dried over anhydrousMgSO₄, and concentrated under reduced pressure. Purification by silicagel column chromatography (EtOAc/MeOH) affords intermediate 2-8.

Preparation of Intermediate 2-9

Intermediate 2-8 (1 mmol, 1.0 mol/eq) is dissolved in anhydrous1,2-dichloroethane (20 mL) containing triethylamine (3.0 mol/eq). Thesolution is cooled in an ice-bath. Under N₂ atmosphere, bromine (1.1eq.) is added very slowly. Stirring is continued at room temperature foradditional 1 h. The reaction mixture is poured slowly into saturatedaqueous sodium bicarbonate solution (50 mL) and separated. The organicphase is washed with water (50 mL×3), brine (50 mL) and dried overNa₂SO₄, filtered, concentrated. The obtained crude mixture is purifiedby silica gel column chromatography to give intermediate 2-9.

Preparation of Compound 2

Intermediate 2-9 (1 mol/eq) is added to a dried round bottom flaskequipped with a stirring bar and 1 M tetrabutylammonium fluoride (TBAF)in THF (2 mol/eq) buffered with a mixture of acetic acid (2.6 mol/eq)and acetic anhydride (2.6 mol/eq). The reaction is monitored by TLCuntil deprotection is complete. The reaction is then quenched with water(3 mol/eq). The reaction mixture is concentrated till dryness undervacuum to give a crude product, which is purified by flashchromatography to afford compound 2.

Example 3 Compound 3 Preparation of isopropyl2-(((6aR,8R,9S,9aS)-8-(6-amino-2-fluoro-9H-purin-9-yl)-9-hydroxy-2,2-dimethyl-4-oxidotetrahydro-6H-furo[3,2-f][1,3,5,2]trioxaphosphocin-4-yl)amino)propanoate(Scheme 3)

Preparation of Intermediate 3-1

In a two neck flask, fludarabine phosphate (0.5 mmol, 1 mol/eq) andisopropyl L-valinate hydrochloride (3 mol/eq) are dissolved in a mixtureof tert-butanol (9 ml) and H₂O (2 ml). Triethylamine (10 mol/eq) areadded to the mixture to facilitate dissolution. An appropriate amount ofN,N′-dicyclohexylcarbodiimide (DCC) (3 mol/eq) is dissolved in 1 ml oftert-butanol and is dropwise added to the reaction mixture. The reactionmixture is refluxed while stirring. The progress of the reaction ismonitored by TLC (i-PrOH:NH₃:H₂O). Upon near completion, the reactionmixture is cooled down and the solvent is removed by rotary evaporationto provide crude intermediate 3-1.

Preparation of Compound 3

To a round bottom flask containing intermediate 3-1 (1 mmol, 1 mol/eq)are added 2,2-dimethoxypropane (30 mL), toluene (30 ml), and PPTS.H₂O (3mol/eq), and the mixture is stirred under reflux under N₂. The reactionis monitored by TLC analysis, and concentrated till dryness upon nearcompletion. Silica gel column chromatography of the crude reactionproduct provided compound 3.

Example 4 Compound 4 Preparation of (2S)-isopropyl2-(((6aR,8R,9aR)-8-(4-amino-2-oxopyrimidin-1(2H)-yl)-9,9-difluoro-4-oxidotetrahydro-6H-furo[3,2-f][1,3,5,2]trioxaphosphocin-4-yl)amino)propanoate(Scheme 4)

Preparation of Intermediate 4-1

To gemcitabine hydrochloride (1 mmol, 1 mol/eq) in anhydrous pyridine(10 mL) stirred at 0° C. under nitrogen are added t-butyldimethylsilylchloride (1.1 mol/eq) and imidazole (1.5 mol/eq). The reaction mixtureis stirred at rt and the reaction progress is monitored by TLC analysis.Upon completion, methanol (8 mL) is added, and the reaction is furtherstirred for 1 h. Volatiles of the reaction are then evaporated undervacuum, and the residue is separated by silica gel column chromatography(EtOAc/hexanes) to provide 5′-O-silylated gemcitabine.

This protected nucleoside is then dissolved in DCM (20 mL), and to theresulting mixture are added DMAP (3 mol/eq) and CbzCl (2.5 mol/eq) at 0°C. under nitrogen. Upon completion (monitored by TLC analysis), thereaction mixture is diluted by addition of DCM (100 mL), and washed with1.0 M HCl aqueous solution and then water. The organic layer iscollected, dried over anhydrous MgSO₄, and concentrated till dryness.The residue is separated by silica gel column chromatography(EtOAc/hexanes) to provide intermediate 4-1.

Preparation of Intermediate 4-2

To a solution of intermediate 4-1 (1 mmol, 1 mol/eq) in anhydrous THF(10 mL) stirred at 0° C. under nitrogen is added triethylaminehydrofluoride (6 mol/eq). The reaction is then warmed up to rt, andcontinued till completion (as monitored by TLC analysis). Volatiles areevaporated under vacuum, and the residue is dissolved in EtOAc (50 mL),washed with cold sodium bicarbonate aqueous solution (30 mL), brine (30mL), and dried over anhydrous MgSO₄ and filtered. The filtrate isconcentrated under vacuum till dryness, and the residue is separated bysilica gel column chromatography (methanol/DCM) to provide intermediate4-2.

Preparation of Intermediate 4-3

To intermediate 4-2 (1 mmol, 1 mol/eq) and DBU (2.4 mol/eq) in anhydrousacetonitrile (20 mL) stirred at 0° C. under nitrogen is slowly addedintermediate 1-2 (1.2 mol/eq) dissolved in DCM (20 mL). Upon completionas indicated by TLC analysis, volatiles are evaporated in vacuo and theresidue is purified by silica gel column chromatography (0 to 5%MeOH/DCM) to afford intermediate 4-3.

Preparation of Intermediate 4-4

Intermediate 4-3 (0.5 mmol, 1 mol/eq) is dissolved in EtOAc-EtOH (1:1,50 mL) in a dried flask, 10% wet palladium-carbon is then added. Themixture is purged with nitrogen twice, and hydrogenated (with a balloonfilled with H₂) at ambient temperature. After completion (monitored byTLC analysis), the solid is removed by filtration. The filtrate isconcentrated by evaporation under vacuum to provide the crude product.Column chromatography on silica gel (MeOH/DCM) affords intermediate 4-4.

Preparation of Compound 4

Intermediate 4-4 (1 mmol, 1.0 mol/eq) is dissolved in anhydrous1,2-dichloroethane (20 mL) containing triethylamine (2.2 mol/eq). Thesolution is cooled in an ice-water bath. Under N₂ atmosphere, bromine(1.1 mol/eq) is added very slowly. Stirring is continued at roomtemperature for additional 1 hour. The reaction mixture is poured slowlyinto saturated aqueous sodium bicarbonate solution (10 mL) andseparated. The organic phase is washed with water (20 mL×3), then brine(20 mL), and dried over Na₂SO₄, filtered, and concentrated till dryness.The obtained crude mixture is purified by silica gel columnchromatography to give the compound 4.

Example 5 Compound 5 Preparation of isopropyl2-(((8aR,10R,11R,11aR)-10-(6-amino-9H-purin-9-yl)-11-hydroxy-11-methyl-6-oxido-2-oxotetrahydro-8H-furo[3,2-h][1,3,5,7,2]tetraoxaphosphecin-6-yl)amino)propanoatee(Scheme 5)

Intermediate 5-1 can be prepared from intermediate 2-4. Cleavage of Bzand BOM by hydrogenation affords compound 5 (Scheme 5).

Example 6 Compound 6 Preparation of isopropyl2-(((7aR,9R,10R,10aR)-9-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-10-fluoro-10-methyl-5-oxido-2-oxohexahydro-2H-furo[3,2-g][1,6,3,2]dioxazaphosphonin-5(9H)-yl)amino)acetate(Scheme 6 A-C)

Intermediate 6-3 can be prepared by a general method similar to that forintermediate 4-4 using Cbz as a transient global protecting group for anucleoside. Lactonization by intramolecular transesterification affordscompound 6 (Scheme 6-A).

Alternatively, 3′-O-aminoacyl can be installed at early stage, andcompound 6 can be synthesized by phosphorylation and then intramolecularphosphoramidate formation (Scheme 6-B), or by one pot phosphorylationand phosphoramidate formation (Scheme 6-C).

Example 7 Biological Assays

The assays to measure antiviral and anti-neoplastic activities of thesecompounds are described below.

A. Assay for Inhibition of HCV RNA Replication:

The compounds of the present invention (such as compound 1, 2, 5, and 6)are evaluated for their ability to affect the replication of Hepatitis CVirus RNA in cultured hepatoma (HuH-7) cells containing a subgenomic HCVReplicon. The details of the assays are described below (WO 2008/079206and WO 2007/027248).

Protocol a (WO 2008/079206):

The assay is an in situ Ribonuclease protection, Scintillation Proximitybased-plate assay (SPA). 10,000-40,000 cells are plated in 100-200 μL ofmedia containing 0.8 mg/mL G418 in 96-well cytostar plates (Amersham).Compounds are added to cells at various concentrations up to 100 μM in1% DMSO at time 0 to 18 h and then cultured for 24-96 h. Cells are fixed(20 min, 10% formalin), permeabilized (20 min, 0.25% Triton X-100/PBS)and hybridized (overnight, 50° C.) with a single-stranded ³³P RNA probecomplementary to the (+) strand NS5B (or other genes) contained in theRNA viral genome. Cells are washed, treated with RNAse, washed, heatedto 65° C. and counted in a Top-Count Inhibition of replication is readas a decrease in counts per minute (cpm).

Human HuH-7 hepatoma cells, which are selected to contain a subgenomicreplicon, carry a cytoplasmic RNA consisting of an HCV 5′ non-translatedregion (NTR), a neomycin selectable marker, an EMCV IRES (internalribosome entry site), and HCV non-structural proteins NS3 through NS5B,followed by the 3′ NTR.

Protocol b (WO 2007/027248):

A human hepatoma cell line (Huh-7) containing replicating HCV subgenomicreplicon with a luciferase reporter gene (luc-ubi-neo) is used toevaluate anti-HCV activity of the compounds. In this assay, level ofluciferase signal correlates with the viral RNA replication directly.The HCV replicon-reporter cell line (NK/luc-ubi-neo) is cultured in DMEMmedium supplemented with 10% fetal bovine serum and 0.5 mg/ml Geneticin(G418). Cells are maintained in a subconfluent state to ensure highlevels of HCV replicon RNA synthesis.

To evaluate the antiviral activity of compounds, serial dilutions areprepared with concentrations ranging from 300 to 0.14 μM. Dilutedcompounds are transferred to a 96-well plate followed by the addition ofreplicon cells (6000 cells per well). Cells are incubated with thecompounds for 48 h after which luciferase activity is measured.Reduction of luciferase signal reflects the decrease of HCV replicon RNAin the treated cells and is used to determine the EC₅₀ value(concentration which yielded a 50% reduction in luciferase activity).

B. The ability of the compounds of the present invention to inhibit HIVinfectivity and HIV spread is measured in the following assays (WO2008/079206).

a. HIV Infectivity Assay

Assays are performed with a variant of HeLa Magi cells expressing bothCXCR4 and CCR5 selected for low background β-galactosidase (β-gal)expression. Cells are infected for 48 h, and β-gal production from theintegrated LHV-1 LTR promoter is quantified with a chemiluminescentsubstrate (Galactolight Plus, Tropix, Bedford, Mass.) Inhibitors aretitrated (in duplicate) in twofold serial dilutions starting at 100 μM;percent inhibition at each concentration is calculated in relation tothe control infection.

b Inhibition of HIV Spread

The ability of the compounds of the present invention to inhibit thespread of the human immunedeficiency virus (BQN) is measured by themethod described in U.S. Pat. No. 5,413,999 (May 9, 1995), and J. P.Vacca, et al., Proc. Natl. Acad. Sci., 91: 4096-4100 (1994), which areincorporated by reference herein in their entirety.

C. The following assays are employed to measure the activity of thecompounds of the present invention against other RNA-dependent RNAviruses:

a. Determination of In Vitro Antiviral Activity of the Compounds AgainstRhinovirus (Cytopathic Effect Inhibition Assay):

Assay conditions are described in the article by Sidwell and Huffman,“Use of disposable microtissue culture plates for antiviral andinterferon induction studies,” Appl. Microbiol. 22: 797-801 (1971).

Viruses:

Rhinovirus type 2 (RV-2), strain HGP, is used with KB cells and media(0.1% NaHCO₃, no antibiotics) as stated in the Sidwell and Huffmanreference. The virus, obtained from the ATCC, is from a throat swab ofan adult male with a mild acute febrile upper respiratory illness.

Rhinovirus type 9 (RV-9), strain 211, and rhinovirus type 14 (RV-14),strain Tow, can be obtained from the American Type Culture Collection(ATCC) in Rockville, Md. RV-9 is from human throat washings and RV-14 isfrom a throat swab of a young adult with upper respiratory illness.

Both of these viruses are used with HeLa Ohio-1 cells which are humancervical epitheloid carcinoma cells. MEM (Eagle's minimum essentialmedium) with 5% Fetal Bovine serum (FBS) and 0.1% NaHCO₃ is used as thegrowth medium. Antiviral test medium for all three virus types is MEMwith 5% FBS, 0.1% NaHCO₃, 50 μg gentamicin/mL, and 10 mM MgCl2- 2000μg/mL is the highest concentration used to assay the compounds of thepresent invention. Virus is added to the assay plate approximately 5 minafter the test compound. Proper controls are also run. Assay plates areincubated with humidified air and 5% CO₂ at 37° C. Cytotoxicity ismonitored in the control cells microscopically for morphologic changes.Regression analysis of the virus CPE data and the toxicity control datagives the ED₅₀ (50% effective dose) and CC₅₀ (50% cytotoxicconcentration). The selectivity index (SI) was calculated by theformula: SI=CC₅₀÷ED₅₀.

b. Determination of In Vitro Antiviral Activity of the Compounds AgainstDengue, Banzi, and Yellow Fever (CPE Inhibition Assay)

Assay details are provided in the Sidwell and Huffman reference above.

Viruses:

Dengue virus type 2, New Guinea strain, can be obtained from the Centerfor Disease Control. Two lines of African green monkey kidney cells areused to culture the virus (Vero) and to perform antiviral testing(MA-104). Both Yellow fever virus, 17D strain, prepared from infectedmouse brain, and Banzi virus, H 336 strain, isolated from the serum of afebrile boy in South Africa, can be obtained from ATCC. Vero cells areused with both of these viruses and for assay.

Cells and Media:

MA-104 cells (BioWhittaker, Inc., Walkersville, Md.) and Vero cells(ATCC) are used in Medium 199 with 5% FBS and 0.1% NaHCO₃ and withoutantibiotics.

Assay medium for dengue, yellow fever, and Banzi viruses is MEM, 2% FBS,0.18% NaHCO₃ and 50 μg gentamicin/mL.

Antiviral testing of the compounds of the present invention is performedaccording to the Sidwell and Huffman reference and similar to the aboverhinovirus antiviral testing. Adequate cytopathic effect (CPE) readingsare achieved after 5-6 days for each of these viruses.

c. Determination of In Vitro Antiviral Activity of Compounds AgainstWest Nile Virus (CPE Inhibition Assay)

Assay details are provided in the Sidwell and Huffman reference citedabove. West Nile virus, New York isolate derived from crow brain, can beobtained from the Center for Disease Control. Vero cells are grown andused as described above. Test medium is MEM, 1% FBS, 0.1% NaHCO₃ and 50μg gentamicin/mL.

Antiviral testing of the compounds of the present invention is performedfollowing the methods of Sidwell and Huffman which are similar to thoseused to assay for rhinovirus activity. Adequate cytopathic effect (CPE)readings are achieved after 5-6 days.

d. Determination of In Vitro Antiviral Activity of Compounds AgainstRhino, Yellow Fever, Dengue, Banzi, and West Nile Viruses (Neutral RedUptake Assay)

After performing the CPE inhibition assays above, an additionalcytopathic detection method is used which is described in “MicrotiterAssay for Interferon: Microspectrophotometric Quantitation of CytopathicEffect,” Appl. Environ. Microbiol. 31: 35-38 (1976). A Model EL309microplate reader (Bio-Tek Instruments Inc.) is used to read the assayplate. ED50's and CD50's were calculated as above.

D. Anti-HBV Assay

Compounds of the present invention can be assayed for anti-HBV activityaccording to any assay known to those of skill in the art.

E. Cytotoxicity Assay:

Protocol a. Cell cultures are prepared in appropriate media atconcentrations of approximately 1.5×10⁵ cells/mL for suspension culturesin 3 day incubations and 5.0×10⁴ cells/mL for adherent cultures in 3 dayincubations. 99 μL of cell culture is transferred to wells of a 96-welltissue culture treated plate, and 1 μL of 100-times final concentrationof the test compound in DMSO is added. The plates are incubated at 37°C. and 5% CO₂ for a specified period of time. After the incubationperiod, 20 μL of CellTiter 96 Aqueous One Solution Cell ProliferationAssay reagent (MTS) (Promega) is added to each well and the plates areincubated at 37° C. and 5% CO₂ for an additional period of time up to 3h. The plates are agitated to mix well and absorbance at 490 nm is readusing a plate reader. A standard curve of suspension culture cells isprepared with known cell numbers just prior to the addition of MTSreagent. Metabolically active cells reduce MTS to formazan. Formazanabsorbs at 490 nm. The absorbance at 490 nm in the presence of compoundis compared to absorbance in cells without any compound added (Cory, A.H. et al, “Use of an aqueous soluble tetrazolium/formazan assay for cellgrowth assays in culture,” Cancer Commun. 3: 207 (1991)).

Protocol b (WO 2007/027248). A Huh-7 cell line carrying a luciferasereporter gene (driven by a HIV LTR promoter) stably integrated into thechromosome is used to analyze the cytotoxic effect of the selectedcompounds. This cell line (LTR-luc) is maintained in DMEM medium with10% FBS. Reduction of luciferase activity in the treated cellscorrelated with the cytotoxic effect of the test compound and is used tocalculate the CC₅₀ value (concentration that inhibited cell growth by50%).

F: Anticancer Assay

Compounds synthesized as anti-cancer agents including compound 3 and 4can each be tested in leukemic cell lines to assess their anticancerefficacy. The compounds can be tested using the MTS assay reagents fromPromega (CellTiter96 Aqueous One solution proliferation assay). Thecompounds can be tested between 10 μM and 0.002 μM in four folddilutions (WO 2006/100439).

Example 8 Assay for the Release of Active Metabolite in Liver Cells

Compounds can be assayed for accumulation in targeted cells of a subjectaccording to any assay known to those of skill in the art. In certainembodiments, a liver cell of the subject can be used to assay for theliver accumulation of compound or a derivative thereof, e.g. anucleoside, nucleoside phosphate or nucleoside triphosphate derivativethereof

Example 9 Pharmaceutical Formulations

As a specific embodiment of an oral composition of a compound of thepresent invention, 50 mg of the compound of Example 1-6 is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size 0 hard gelatin capsule.

While the invention has been described and illustrated in reference tospecific embodiments thereof, those skilled in the art will appreciatethat various changes, modifications, and substitutions can be madetherein without departing from the spirit and scope of the invention.For example, effective dosages other than the preferred doses as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the human being treated for severity of the viralinfection. Likewise, the pharmacologic response observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended therefore that the invention be limited only by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of formula I, its stereoisomers,isotope-enriched analogues, pharmaceutically acceptable salts, hydrates,solvates, or crystalline or polymorphic forms thereof, wherein:

R is a moiety derivable by removal of 3′- and 5′-hydroxyl radicals froma therapeutic nucleoside or its equivalents; A₃ at 5′ is selected asfollows: (i) A₃ is O, S, Se, or NR⁶ where R⁶ is H, OR^(6′), alkyl, aryl,COR^(6′), or CO₂R^(6′), where R^(6′) is H, alkyl, aryl, or heteroaryl;(ii) A₃CH₂ can be optionally replaced with CH₂A₃, or CF₂A₃, so as torepresent a phosphonate or phosphonamidate; PR⁰ is selected as follows:(i) phosphate, or phosphoramidate represented by PY₄R² where Y₄ is O, S,Se, or NR^(8′″); (ii) phosphoramidate of amino acid esters or amides, orof esters or amides of modified amino acids, represented byPY₁[C(R^(1a)R^(1b))]_(d)C(═X₂)Y₄R² where Y₁ is NR⁸, X₂ is O, S or Se,and Y₄ is O, S, Se, or NR^(8′″); X₁ is O, S or Se; M is a molecularbridge selected from CR^(5a)R^(5b), (CR^(5a)R^(5b))_(d)OC(═O), and(CR^(5a)R^(5b))_(d)C(═O), where d is 1 to 4; Y₁, Y₂, Y₃, and Y₄ areselected as follows: (i) Y₁ is selected from O, S, Se, and NR⁸; (ii) Y₂is selected from O, S, Se, and NR^(8′); (iii) Y₃ is selected from O, S,Se, and NR^(8″); (iv) Y₄ is selected from O, S, Se, and NR^(8′″); (v) R⁸and R^(1a) or R^(1b) together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4, and Y₁ isNR⁸; (vi) R^(8′) and R^(5a) or R^(5b) together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4 and Y₂ is NR^(8′); (vii) R^(8″) and R^(5a) or R^(5b) together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, where n is 2 to 4, and Y₃ is NR^(8″); (viii) Y₃ is O, and Y₂ isNR^(8′), so that Y₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a naturalor modified α-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S;(ix) the said modified α-amino acids can be a β-, γ-, or δ-amino acid orits analogues represented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2to 4; (x) Y₂ can be O or S of an α-amino acid residue as in serine (OH),threonine (OH), and cysteine (SH), and the amino can be substituted orunsubstituted; R², R⁸, R^(8′), R^(8″), and R^(8′″) is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionally substituted with a loweralkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl, C₁-C₁₀ haloalkyl, C₃-C₁₀cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aryl such as phenyl,heteroaryl such as pyridinyl, substituted aryl, or substitutedheteroaryl; R⁸ (R^(8′), R^(8″), or R^(8″)) in Y_(x) can be the same ordifferent groups where x is 1 to 4; R^(1a) and R^(1b) are selected asfollows: (i) R^(1a) and R^(1b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)NR^(1′) ₂, hydroxy(C₁-C₆)alkyl,—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″), aryl, heteroaryl,arylalkyl(C₁-C₃), and heteroarylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or alkyl,which includes, but is not limited to, C₁-C₂₀ alkyl, and R^(1″) is—OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; or (iii) R^(1b)is H and R^(1a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH,CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; (iv) R^(1a) and R^(1b) both are C₁-C₆ alkyl; (v)R^(1a) and R^(1b) together are (CH₂)_(m) so as to form a spiro ring,where m is 2 to 5; (vi) R^(1a) is hydrogen and R^(1b) and R⁸ togetherare (CH₂)_(n) so as to form a cyclic ring that includes the adjoining Nand C atoms, where n is 2 to 4 and Y₁ is NR⁸; (vii) R^(1b) is hydrogenand R^(1a) and R⁸ together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4 and Y₁ isNR⁸; R^(5a) and R^(5b) are selected as follows: (i) R^(5a), R^(5b) areindependently selected from hydrogen, C₁-C₁₀ alkyl, cycloalkyl,—(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆), —CH₂SH, —(CH₂)₂S(═O)_(d)Me,—(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,—(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃), where c is 1 to 6, d is 0to 2, e is 0 to 3, and said aryl groups are optionally substituted witha group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆ alkoxy, halogen,nitro and cyano, and where R^(1′) is independently hydrogen or C₁-C₆alkyl and R^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(5a) and R^(5b) bothare C₁-C₆ alkyl; (iii) R^(5a) and R^(5b) together are (CH₂)_(m) so as toform a spiro ring, where m is 2 to 5; (iv) R^(5a) is hydrogen and R^(5b)and R^(8′) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₂ is NR^(8′), and n is 2 to4; (v) R^(5b) is hydrogen and R^(5a) and R^(8′) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₂ is NR^(8′), and n is 2 to 4; (vi) R^(5a) is hydrogen and R^(5b)and R^(8″) together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms where Y₃ is NR^(8′), and n is 2 to4; (vii) R^(5b) is hydrogen and R^(5a) and R^(8″) together are (CH₂)_(n)so as to form a cyclic ring that includes the adjoining N and C atoms,where Y₃ is NR^(8″), and n is 2 to 4;
 2. The compound of claim 1(Formula I-1), its stereoisomers, isotope-enriched analogues,pharmaceutically acceptable salts, hydrates, solvates, or crystalline orpolymorphic forms thereof, wherein the bc-ProTide is represented as inI-1:

Q is any nucleic acid base or its analogues, either a naturallyoccurring or modified purine or pyrimidine base. Non-limiting examplesinclude:

wherein: (i) Z is N or CR¹⁶; (ii) R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, SeH, SeR′, NH₂,NHR′, NR′₂, NHNH₂, NR′NH₂, NR′NHR′, NHNR′₂, NR′NR′₂, lower alkyl ofC₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl ofC₂-C₆, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynylof C₂-C₆, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, loweralkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′ is anoptionally substituted alkyl, which includes, but is not limited to, anoptionally substituted C₁-C₂₀ alkyl, an optionally substituted loweralkyl, an optionally substituted cycloalkyl, an optionally substitutedalkynyl of C₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted sulfonyl, or optionally substituted acyl, whichincludes but is not limited to C(═O) alkyl, or alternatively, in theinstance of NR′₂, each R′ comprise at least one C atom that are joinedto form a heterocycle comprising at least two carbon atoms; (iii) Y₅ isselected from O, S, and Se; (iv) R¹⁶ is H, halogen (including F, Cl, Br,I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, NO₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxyof C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′,C(═O)NH₂, C(═O)NHR′, C(═O)NR′₂, CH═CHCO₂H, or CH═CHCO₂R′, aryl, orheteroaryl; A₁ is selected from O, S, Se, NR⁶, C═CH₂, and CR^(7a)R^(7b),where (i) R⁶ is R^(6′) or COR^(6′) where R^(6′) is H, alkyl, aryl,heteroaryl, OH, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino,or heteroarylamino, and R^(7a) and R^(7b) are independently selectedfrom H, OH, SH, F, Cl, alkyl, aryl, and heteroaryl; (ii) CR^(7a)R^(7b)is C(CH₂)_(m) so as to form a spiro ring where m is 2 to 5, or is asubstituted or unsubstituted spiro epoxide, aziridine, or oxetane; (iii)R⁴ is CH₂ so as to form a substituted bicyclo[3.1.0]hexane includingA₁CR⁴; A₂R³W is selected as follows: (i) A₂R³W is (H)₂ (so as to form anacyclic nucleoside), CH₂, C═CH₂, or C═CR^(7a)R^(7b) where R^(7a) andR^(7b) are defined as in (a); (ii) A₂R³W is C(CH₂)_(m) where m is 2 to 5so as to form a spiro ring or is a substituted or unsubstituted spiroepoxide, aziridine, or oxetane; W is H, F, halogen, OH, OMe, NHR⁶ or N₃where A₂R³ is CR³, and R⁶ is R^(6′) or COR^(6′) where R^(6′) is H,alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, or heteroarylamino; R³ is H, CH₃, CH₂F, CHF₂, CF₃, F, CN,C₁-C₆ alkyl, aryl or heteroaryl, where A₂W is CW; R^(3′) is H, CH₃,CH₂F, CHF₂, CF₃, F, CN, C₁-C₆ alkyl, aryl, alkoxy carbonyl, orthioalkoxy carbonyl, C₁-C₁₀ alkylcarbamoyl (C₁-C₁₀ alkylaminocarbonyl),arylcarbamoyl, or heteroarylcarbamoyl; A₃ is selected as follows: (i) A₃is O, S, Se, or NR⁶ where R⁶ is H, OR^(6′), alkyl, aryl, COR^(6′), orCO₂R^(6′), where R^(6′) is H, alkyl, aryl, or heteroaryl; (ii) A₃CH₂ canbe optionally replaced with CH₂A₃, or CF₂A₃, so as to represent aphosphonate or phosphonamidate; L and R⁴ are independently selected fromH, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl(i.e., —(CH₂)_(p)OH, where p is 1 to 6, including hydroxyl methyl(CH₂OH)), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkynyl(optionally substituted), or halogen, including F, Cl, Br, or I; PR⁰ isselected from: (i) phosphate, or phosphoramidate represented by PY₄R²where Y₄ is O, S, Se, or NR^(8′″); (ii) phosphoramidate of amino acidesters or amides, or of esters or amides of modified amino acids,represented by PY₁[C(R^(1a)R^(1b))]_(d)C(═X₂)Y₄R² where Y₁ is NR⁸, X₂ isO, S or Se, and Y₄ is O, S, Se, or NR^(8′″); X₁ is O, S or Se; M is amolecular bridge selected from CR^(5a)R^(5b), (CR^(5a)R^(5b))_(d)OC(═O),and (CR^(5a)R^(5b))_(d)C(═O), where d is 1 to 4; Y₁, Y₂, Y₃, and Y₄ areselected as follows: (i) Y₁ is selected from O, S, Se, and NR⁸; (ii) Y₂is selected from O, S, Se, and NR^(8′); (iii) Y₃ is selected from O, S,Se, and NR^(8″); (iv) Y₄ is selected from O, S, Se, and NR^(8′″); (v) R⁸and R^(1a) or R^(1b) together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where n is 2 to 4, and Y₁ isNR⁸; (vi) R^(8′) and R^(5a) or R^(5b) together are (CH₂)_(n) so as toform a cyclic ring that includes the adjoining N and C atoms, where n is2 to 4 and Y₂ is NR^(8′); (vii) R^(8″) and R^(5a) or R^(5b) together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, where n is 2 to 4, and Y₃ is NR^(8″); (viii) Y₃ is O, and Y₂ isNR⁸, so that Y₂CR^(5a)R^(5b)C(═O)Y₃ represents an ester of a natural ormodified α-amino acid such as glycinyl (NHCH₂CO₂), or Y₂ is O or S; (ix)the said modified α-amino acids can be a β-, γ-, or δ-amino acid or itsanalogues represented by Y₂(CR^(5a)R^(5b))_(d)C(═O)Y₃ where d is 2 to 4;(x) Y₂ can be O or S of an α-amino acid residue as in serine (OH),threonine (OH), and cysteine (SH), and the amino can be substituted orunsubstituted; R², R⁸, R^(8′), R^(8″), and R^(8′″) are independentlyselected from hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl optionallysubstituted with a lower alkyl, alkoxyalkyl, di(lower alkyl)-aminoalkyl,C₁-C₁₀ haloalkyl, C₃-C₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aryl such as phenyl, heteroaryl such as pyridinyl, substituted aryl, orsubstituted heteroaryl; R⁸ (R^(8′), R^(8″), or R^(8″)) in Y_(x) can bethe same or different groups where x is 1 to 4; R^(1a) and R^(1b) areselected as follows: (i) R^(1a) and R^(1b) are independently selectedfrom hydrogen, C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)NR^(1′) ₂,hydroxy(C₁-C₆)alkyl, —CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂,(1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″),aryl, heteroaryl, arylalkyl(C₁-C₃), and heteroarylalkyl(C₁-C₃), where cis 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups are optionallysubstituted with a group selected from hydroxyl, C₁-C₁₀ alkyl, C₁-C₆alkoxy, halogen, nitro and cyano, and where R¹ is independently hydrogenor alkyl, which includes, but is not limited to, C₁-C₂₀ alkyl, andR^(1″) is —OR^(1′) or —N(R^(1′))₂; (ii) R^(1a) is H and R^(1b) is H,CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H,CH₂C(═O)NH₂, CH₂CH₂COOH, CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph, CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, orlower cycloalkyl; or (iii) R^(1b) is H and R^(1a) is H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂-indol-3-yl,—CH₂CH₂SCH₃, CH₂OH, CH(OH)CH₃, CH₂SH, CH₂CO₂H, CH₂C(═O)NH₂, CH₂CH₂COOH,CH₂CH₂C(═O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(═NH)NH₂, CH₂Ph,CH₂((4′-OH)-Ph), CH₂-imidazol-4-yl, or lower cycloalkyl; (iv) R^(1a) andR^(1b) both are C₁-C₆ alkyl; (v) R^(1a) and R^(1b) together are(CH₂)_(m) so as to form a spiro ring, where m is 2 to 5; (vi) R^(1a) ishydrogen and R^(1b) and R⁸ together are (CH₂)_(m) so as to form a cyclicring that includes the adjoining N and C atoms, where n is 2 to 4 and Y₁is NR⁸; (vii) R^(1b) is hydrogen and R^(1a) and R⁸ together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, where n is 2 to 4 and Y₁ is NR⁸; R^(5a) and R^(5b) are selectedas follows: (i) R^(5a), R^(5b) are independently selected from hydrogen,C₁-C₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(1′))₂, hydroxyalkyl (C₁-C₆),—CH₂SH, —(CH₂)₂S(═O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(1″), aryl and arylalkyl(C₁-C₃),where c is 1 to 6, d is 0 to 2, e is 0 to 3, and said aryl groups areoptionally substituted with a group selected from hydroxyl, C₁-C₁₀alkyl, C₁-C₆ alkoxy, halogen, nitro and cyano, and where R^(1′) isindependently hydrogen or C₁-C₆ alkyl and R^(1″) is —OR^(1′) or—N(R^(1′))₂; (ii) R^(5a) and R^(5b) both are C₁-C₆ alkyl; (iii) R^(5a)and R^(5b) together are (CH₂)_(m) so as to form a spiro ring, where m is2 to 5; (iv) R^(5a) is hydrogen and R^(5b) and R^(8′) together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms where Y₂ is NR^(8′), and n is 2 to 4; (v) R^(5b) is hydrogen andR^(5a) and R^(8′) together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where Y₂ is NR⁸, and n is 2to 4; (vi) R^(5a) is hydrogen and R^(5b) and R^(8″) together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms where Y₃ is NR^(8′), and n is 2 to 4; (vii) R^(5b) is hydrogenand R^(5a) and R^(8″) together are (CH₂)_(n) so as to form a cyclic ringthat includes the adjoining N and C atoms, where Y₃ is NR^(8″), and n is2 to 4;
 3. The compound of claim 1 (Formula II), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by II:


4. The compound of claim 1 (Formula III), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by III:


5. The compound of claim 1 (Formula IV), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by IV:


6. The compound of claim 1 (Formula V), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by V:


7. The compound of claim 1 (Formula VI), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by VI:


8. The compound of claim 1 (Formula VII), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by VII:


9. The compound of claim 1 (Formula VIII), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by VIII:


10. The compound of claim 1 (Formula IX), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by IX:


11. The compound of claim 1 (Formula X), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form, wherein the bc-ProTide isrepresented by X:


12. The compound of claim 1 (Formula XI), its stereoisomers,isotope-enriched 0analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form, wherein the bc-ProTide isrepresented by XI:


13. The compound of claim 1 (Formula XII), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XII:


14. The compound of claim 1 (Formula XIII), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XIII:


15. The compound of claim 1 (Formula XIV), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XIV:


16. The compound of claim 1 (Formula XV), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XV:


17. The compound of claim 1 (Formula XVI), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form, wherein the bc-ProTide isrepresented by XVI:


18. The compound of claim 1 (Formula XVII), its stereoisomers,isotope-enriched 0analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form, wherein the bc-ProTide isrepresented by XVII:


19. The compound of claim 1 (Formula XVIII), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XVIII:


20. The compound of claim 1 (Formula XIX), its stereoisomers,isotope-enriched analogue, pharmaceutically acceptable salt, hydrate,solvate, or crystalline or polymorphic form thereof, wherein thebc-ProTide is represented by XIX:


21. A pharmaceutical composition comprising one or more of compounds inclaim 1, optionally in combination with a pharmaceutically acceptablecarrier, additive or excipient.
 22. The use of compounds in claim 21includes, but not limited by, the use for the treatment of viralinfections and/or neoplastic diseases in mammals.
 23. The pharmaceuticalcomposition according to claim 21 further in combination with at leastone additional antiviral agent.